Methods for inhibiting bone loss

ABSTRACT

The present invention provides methods of inhibiting bone loss in mammals via the administration to a mammal in need of such treatment an effective amount of a compound from a series of benzoquinolin-3-ones. Such compounds also are sequentially or concurrently coadministered with a bone antiresorptive agent or a bone anabolic agent.

The present invention relates to the fields of pharmacology andpharmaceutical chemistry, and provides methods for inhibiting the lossof bone in humans.

The mechanism of bone loss is not well understood, but in practicaleffect, the disorder arises from an imbalance in the formation of newhealthy bone and the resorption of old bone, skewed toward a net loss ofbone tissue. This bone loss includes a decrease in both mineral contentand protein matrix components of the bone, and leads to an increasedfracture rate of, predominantly, femoral bones and bones in the forearmand vertebrae. These fractures, in turn, lead to an increase in generalmorbidity, a marked loss of stature and mobility, and, in many cases, anincrease in mortality resulting from complications.

Bone loss occurs in a wide range of subjects including post-menopausalwomen, patients who have undergone hysterectomy, patients who areundergoing or have undergone long-term administration ofcorticosteroids, patients suffering from Cushing's syndrome, and patentshaving gonadal dysgenesis.

Unchecked, bone loss can lead to osteoporosis, a major debilitatingdisease whose prominent feature is the loss of bone mass (decreaseddensity and enlargement of bone spaces) without a reduction in bonevolume, producing porosity and fragility.

One on the most common types of osteoporosis is found in post-menopausalwomen affecting an estimated 20 to 25 million women in the united Statesalone. A significant feature of post-menopausal osteoporosis is thelarge and rapid loss of bone mass due to the cessation of estrogenproduction by the ovaries. Indeed, data clearly support the ability ofestrogens to limit the progression of osteoporotic bone loss, andestrogen replacement is a recognized treatment for postmenopausalosteoporosis in the United States and many other countries. Although theadministration of estrogens have beneficial effects on bone when giveneven at very low levels, long-term estrogen therapy has been implicatedin a variety of disorders such as an increase in the risk of uterine andbreast cancer, causing many women to avoid this treatment. Recentlysuggested therapeutic regimens which seek to lessen the cancer risk,such as administering combinations of progestogen and estrogen, causethe patient to experience regular withdrawal bleeding which isunacceptable to most older women. Concerns over the significantundesirable effects associated with estrogen therapy, and the limitedability of estrogens to reverse existing bone loss, support the need todevelop alternative therapy for bone loss that generates the desirableeffects on bone but does not cause undesirable effects.

Attempts to fill this need by the use of compounds commonly known asantiestrogens, which interact with the estrogen receptor, have hadlimited success, perhaps due to the fact that these compounds generallydisplay a mixed agonist/antagonist effect. That is, although thesecompounds can antagonize estrogen interaction with the receptor, thecompounds themselves may cause estrogenic responses in those tissueshaving estrogen receptors. Therefore, some antiestrogens, whenadministered alone, are subject to the same adverse effects associatedwith estrogen therapy.

Accordingly, the present invention provides methods for inhibiting theloss of bone without the associated adverse effects of hormonereplacement therapy, and thus, serves an an effective acceptabletreatment for osteoporosis. The primary pharmaceutical agents used forthe methods of the present invention are known to inhibit the activityof the enzyme 5α-reductase (5AR), such inhibition demonstrating theability of these agents to inhibit bone loss in humans. The inhibitionof bone loss contemplated by the present methods includes both medicaltherapeutic and/or prophylactic treatment, as appropriate.

For some time, the enzyme 5α-reductase (5AR) has been known to beimportant in the physiological mechanisms related to testosterone and5α-dihydrotestosterone. It is known that 5α-dihydrotestosterone is anextremely potent androgen and it has been known or suspected that it isinvolved in the mechanisms of benign prostatic hyperplasia and malepattern baldness among other disorders and diseases. One 5AR inhibitor,finasteride, is now approved in the United States and other countriesfor the treatment of benign prostatic hyperplasia.

Recently, it has been found that there are at least two 5AR isozymes inthe human, Andersson, et al., Proc. Natl. Acad. Sci. USA, 87:3640-44(1990); Andersson, et al., Nature, 354, 159-61 (1991). The isozymes,usually called Type I and Type II, exhibit differences in theirbiochemical properties, genetics, and pharmacology. Both isozymes arenow the subject of considerable research and it has been found that TypeI is more prevalent in the scalp, and that Type II is more prevalent inthe prostate.

It has been discovered that Type I 5AR is the form of the enzyme whichis active in one of the processes which affect the formation/resorptionof bone. By inhibiting the enzymatic activity of Type I 5α-reductase,bone loss is inhibited via a plurality of biological pathways. Thus, itis now possible to provide methods of inhibiting bone loss, particularlyin humans via the methods of the present invention.

The present invention, therefore, provides a method for inhibiting boneloss, particularly in humans, via the administration of a 5AR inhibitingcompound of formula I below.

Because one of the biological pathways of inhibiting the activity ofType 5AR in bone results in an anabolic response (an increase in thebone-forming protein matrix) it would also be beneficial tocoadminister, either concurrently or sequentially, an antiresorptioncompound. Thus, the present invention also provides a method ofinhibiting bone loss via the coadministration of a Type I 5AR inhibitingcompound of formula I below and a bone antiresorption pharmaceuticalagent.

Furthermore, the inhbition of Type I 5AR results in an increase inavailable testosterone which is a known precursor to estradiol.Increased indigenous estradiol levels will contribute to the inhibitionof bone resorption, but it would be beneficial to coadminister, eitherconcurrently or sequentially, an additional bone anabolic agent such asparathyroid hormone (PTH) or an analog thereof. Thus, the presentinvention further provides a method of inhibiting bone loss via thecoadministration of a Type I 5AR inhibiting compound of formula I belowand a bone anabolic agent.

One aspect of the present invention provides a method for inhibitingbone loss comprising administering to a mammal in need of treatment aneffective amount of a compound of formula I ##STR1## wherein

R and R¹ both represent hydrogen or combine to form a bond;

R² represents hydrogen or C₁ -C₃ alkyl;

R³ represents hydrogen, methyl or ethyl; either R⁴ and X--R⁵ have thefollowing definitions, (R⁶)_(m) is absent, and R³ does not representhydrogen; or (R⁶)_(m) has the following definition, R⁴ and X--R⁵ areabsent, and R³ does not represent ethyl;

R⁴ and --X--R⁵ each occupies one of the 7-, 8- and 9-positions;

R⁴ represents hydrogen, halo, methyl or ethyl;

X represents C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₂ -C₄ alkynyl, a bond,--SO--, --SO₂ --, --CO--Y--(CH₂)_(n) --, --Y--CO--(CH₂)_(n), --CO--,--Z--(CH₂)_(n) --, or --SO₃ --; wherein X groups which are notsymmetrical may be in either orientation;

Y represents --S--, --O--, or --NH--;

Z represents --O-- or --S--;

n represents 0-3;

R⁵ represents phenyl, naphthalenyl, pyridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, anthracenyl, acenaphthalenyl, thiazolyl, benzimidazolyl,indazolyl, thiophenyl, phenanthrenyl, quinolinyl, fluorenyl,isoquinolinyl, indanyl, benzopyranyl, indolyl, benzisoquinolinyl,benzindolyl, benzothiazolyl, benzothiophenyl, quinoxalinyl,benzoxazolyl, tetrazolyl, naphthothiazolyl, quinazolinyl,thiazolopyridinyl, pyridazinoquinazolinyl, benzisothiazolyl,benzodioxolyl, benzodioxinyl, diphenylmethyl or triphenylmethyl;

the above R⁵ groups are unsubstituted or substituted with 1-3 groupschosen from the group consisting of halo, trifluoromethyl,trifluoroethoxy, C₁ -C₄ alkyl, trifluoromethoxy, hydroxy, C₁ -C₃ alkoxy,nitro, C₁ -C₃ alkylthio, C₁ -C₆ alkanoyl, phenyl, oxo, phenoxy,phenylthio, C₁ -C₃ alkylsulfinyl, C₁ -C₃ alkylsulfonyl, cyano, amino, C₁-C₃ alkylamino, diphenylmethylamino, triphenylmethylamino, benzyloxy,benzylthio, (mono-halo, nitro or CF₃)benzyl(oxy or thio), di(₁ -C₃alkyl, C₃ -C₆ cycloalkyl, or C₄ -C₈ cycloalkylalkyl)amino, (mono-C₁ -C₃alkyl, C₁ -C₃ alkoxy or halo)-(phenyl, phenoxy, phenylthio,phenylsulfonyl or phenoxysulfonyl), C₂ -C₆ alkanoylamino, benzoylamino,diphenylmethylamino(C₁ -C₃ alkyl), aminocarbonyl, C₁ -C₃alkylaminocarbonyl, di(C₁ -C₃ alkyl)aminocarbonyl, halo-C₁ -C₆ alkanoyl,aminosulfonyl, C₁ -C₃ alkylaminosulfonyl, di(C₁ -C₃ alkyl)aminosulfonyl,phenyl(oxy or thio)(C₁ -C₃ alkyl), (halo, C₁ -C₃ alkyl or C₁ -C₃alkoxy)phenyl(oxy or thio)(C₁ -C₃ alkyl), benzoyl, or (amino, C₁ -C₃alkylamino or di(C₁ -C₃ alkyl)amino) (C₁ -C₃ alkyl);

or an above R⁵ group is substituted with a morpholino (C₁ -C₃ alkyl)group, a phenyl (C₁ -C₃ alkyl)piperidinyl group, a phenyl (C₁ -C₃alkyl)-piperidinylaminocarbonyl group, a C₂ -C₆ alkanoyl-aminothiophenylgroup, or a (amino, C₁ -C₃ alkylamino or di(C₁ -C₃alkyl)amino)naphthalenylsulfonylamino group;

or R⁵ is a perhalophenyl group;

m represents 1-2;

R⁶ represents hydrogen, halogen, NO₂, cyano, CF₃, C₁ -C₃ alkyl, C₁ -C₆alkoxy, carboxy, C₁ -C₆ alkoxycarbonyl, amino, C₁ -C₄ alkylamino, C₁ -C₄dialkylamino, amido, C₁ -C₄ alkylamido, C₁ -C₄ dialkylamido, mercapto,C₁ -C₆ alkylthio, C₁ -C₆ alkylsulfinyl, C₁ -C₆ alkylsulfonyl, or a group--A--R⁷ where A represents C₁ -C₆ alkylene, C₂ -C₆ alkenylene or C₂ -C₆alkynylene; and R⁷ represents halogen, hydroxy, CF₃, C₁ -C₆ alkoxy,carboxy, C₁ -C₆ alkoxycarbonyl, amino, C₁ -C₄ alkylamino, C₁ -C₄dialkylamino, amido, C₁ -C₄ alkylamido, C₁ -C₄ dialkylamido, C₁ -C₄alkylsulfonylamino, aminosulfonyl or C₁ -C₄ alkylaminosulfonyl;

or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention provides the above-describedmethod, and further comprises the coadministration of an antiresorptiveagent and/or an anabolic agent.

Throughout the present document, all temperatures will be described indegrees Celsius and all expressions of concentration, percentage andproportion will be expressed in weight units, except for mixtures ofsolvents, which will be described in volume units, unless otherwisestated.

References to compounds of formula I in this document include thepharmaceutically acceptable salts of such compounds, unless otherwisestated.

The Compounds

The compounds of Formula I wherein X--R⁵ and R⁴ are absent, and (R⁶)_(m)represents certain groups, and compound A as well, have been disclosedin U.S. Pat. No. 5,239,075 and European Patent Office Publication0532100. That U.S. patent is herein incorporated by reference and thereader should refer to it for the description, synthesis and biologicalactivities of that group of compounds.

The compounds wherein (R⁶)_(m) is absent and X--R⁵ and R⁴ are asdescribed above, have not previously been published, and so that groupof compounds will be described in full.

The various positions on the benzo[f]quinoline ring are indicated below.##STR2##

The spatial configuration of the group R³ at 10b and the hydrogen atomat 4a are required, and the synthetic methods for obtaining thatconfiguration will be shown. The reader will understand that most of thecompounds can exist in two stereochemical forms, or even more dependingon the nature of the R⁵ group, and that all stereochemical forms areincluded in the present invention. In some of the compounds prepared ordescribed below, single enantiomers are prepared in pure form and areidentified by (+) or (-) nomenclature. In other cases, the mixture ofenantiomers is prepared.

(Compounds Where R⁴ and X--R⁵ are Absent)

These compounds, as well as compound A, are well disclosed in U.S. Pat.No. 5,239,075, and so only some discussion of the compounds which areparticularly preferred for the present methods is necessary here.

A preferred group of such compounds includes those of formula I wherein:

R and R¹ are hydrogen;

R⁶ is halogen, CF₃, C₁ -C₆ alkyl, C₁ -C₄ alkoxy or --A--R⁷ where A is C₁-C₄ alkylene and R⁷ is C₁ -C₄ alkoxy-carbonyl.

A more preferable group of such compounds includes those wherein:

R² is hydrogen or methyl;

R and R¹ are hydrogen;

R⁶ is halogen, CF₃ or C₁ -C₄ alkyl.

Particularly preferred such compounds are as follows:

(-)-(4aR)-(10bR)-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

(+)-(4aR)-(10bR)-8-chloro-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

8-chloro-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

(+)-(4aR)-(10bR)-8,9-dichloro-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

(Compounds Where (R⁶)_(m) is Absent)

The groups R⁴ and X--R⁵ may occupy either the 7, 8, or 9-position.

The term "halo" includes chloro, bromo and fluoro.

The various alkyl groups, such as C₁ -C₃ alkyl, C₁ -C₄ alkyl and thelike include groups such as methyl, ethyl, propyl, isopropyl, t-butyl,butyl and isobutyl. When such groups link other portions of a molecule,they are bivalent and the location of the linkages will be indicated inthe chemical name.

Alkenyl and alkynyl groups constitute linking groups which are bivalentand are bonded to two other groups. For example, C₂ -C₄ alkenyl includes2-propenyl, 3-butenyl and 2-butenyl; and C₂ -C₄ alkynyl includes, forexample, ethynyl, 2-propynyl, 2-butynyl and iso-2-butynyl.

The groups C₁ -C₆ alkanoyl and C₂ -C₆ alkanoyl include such groups asformyl, acetyl, propionyl, isobutyryl, 2-ethylpropionyl and hexanoyl.The group C₃ -C₆ cycloalkyl includes cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl, and the group C₄ -C₈ cycloalkylalkylincludes, for example, cyclopropylmethyl, cyclohexylethyl,cyclobutylbutyl and cyclohexylmethyl.

Terms such as C₁ -C₃ alkoxy, C₁ -C₃ alkylsulfonyl, benzylthio, phenoxy,and C₁ -C₃ alkylamino refer to the indicated alkyl, benzyl or the likegroup linked to an oxygen atom, sulfur atom, sulfonyl group or aminogroup as indicated.

Terms such as halo-C₁ -C₆ alkanoyl, halophenyl or C₁ -C₃ alkylphenylrefer to the indicated basic group having substituted on it 1, 2, or 3halo or C₁ -C₃ alkyl groups as may be described in the individual case.

The term perhalophenyl refers to a phenyl group which is fullysubstituted at all available positions with halogen atoms.

The compounds of formula I all have the benzo[f]-quinoline nucleus, onthe phenyl ring of which is substituted a cyclic group, frequently anarylcyclic group, which is linked to the benzoquinoline through the Xlinker, which in many cases is simply a bond. The R⁵ groups may besubstituted with additional organic groups, and may bear as many asthree of the indicated substituent groups. Multiple substituents may allbe the same, as, for example, 2,3,5-trifluorophenyl, or may bedifferent, such as, for example, 3,5-bis(t-butyl)-4-hydroxyphenyl. Thespecifically named compounds which appear below in this document willfurther illustrate the contemplated X, R⁵ and substituent groups.

The X groups which are not symmetrical may be in either orientation onthe molecule; for example, the atom Z of the group --Z--(CH₂)_(n) -- maybe adjacent either to R⁵ or to the phenyl ring of the nucleus of formulaI.

The cyclic R⁵ groups may take any permissible orientation. For example,the following specific R⁵ groups are contemplated.

phenyl

2-quinolinyl

4-quinolinyl

7-quinolinyl

1-isoquinolinyl

3-isoquinolinyl

8-isoquinolinyl

2-quinoxalinyl

5-quinoxalinyl

7-quinoxalinyl

2-benzothiazolyl

4-benzothiazolyl

6-benzothiazolyl

7-1H-indazolyl

3-1H-indazolyl

5-2H-indazolyl

2-2H-indazolyl

7-2H-indazolyl

4-3H-indazolyl

3-3H-indazolyl

1-indolyl

3-indolyl

3-2H-indolyl

2-3H-indolyl

6-2H-indolyl

4-3H-indolyl

2-benzoxazolyl

5-benzoxazolyl

3-1,2-benzisothiazolyl

5-1,2-benzisothiazolyl

7-2,1-benzisothiazolyl

4-2,1-benzisothiazolyl

2-pyridinyl

4-pyridinyl

3-pyridazinyl

5-pyridazinyl

2-pyrazinyl

5-pyrazinyl

2-naphtho[2,3-d]thiazolyl

8-naphtho[2,3-d]thiazolyl

6-naphtho[2,3-d]thiazolyl

1-naphtho[2,1-d]thiazolyl

5-naphtho[2,1-d]thiazolyl

2-naphtho[1,2-d]thiazolyl

6-naphtho[1,2-d]thiazolyl

1-naphthalenyl

2-naphthalenyl

2-thienyl

3-thienyl

1-anthracenyl

10-anthracenyl

6-anthracenyl

1-phenanthrenyl

4-phenanthrenyl

9-phenanthrenyl

1-3H-fluorenyl

3-3H-fluorenyl

9-3H-fluorenyl

1-fluorenyl

5-fluorenyl

1-acenaphthalenyl

5-acenaphthalenyl

diphenylmethyl

triphenylmethyl

2-thiazolyl

4-thiazolyl

2-benzimidazolyl

6-benzimidazolyl

1-indanyl

4-indanyl

3-2H-1-benzopyranyl

7-2H-1-benzopyranyl

2-chromanyl

5-chromanyl

4-4H-1-benzopyranyl

8-4H-1-benzopyranyl

3-5H-1-benzopyranyl

5-5H-1-benzopyranyl

1-benz[g]isoquinolinyl

5-benz[g]isoquinolinyl

8-benz[g]isoquinolinyl

4-benz[h]isoquinolinyl

10-benz[h]isoquinolinyl

2-benz[f]isoquinolinyl

6-benz[f]isoquinolinyl

3-1H-benz[de]isoquinolinyl

9-1H-benz[de]isoquinolinyl

4-4H-benz[de]isoquinolinyl

6-4H-benz[de]isoquinolinyl

1-1H-benz[f]indolyl

4-1H-benz[f]indolyl

2-3H-benz[f]indolyl

7-3H-benz[f]indolyl

2-pyrimidinyl

5-pyrimidinyl

1-3H-carbazolyl

5-3H-carbazolyl

3-4aH-carbazolyl

4a-4aH-carbazolyl

2-8aH-carbazolyl

7-8aH-carbazolyl

8-carbazolyl

4-carbazolyl

2-1H-benz[g]indolyl

6-1H-benz[g]indolyl

3-3H-benz[g]indolyl

9-3H-benz[g]indolyl

1-1H-benz[e]indolyl

5-1H-benz[e]indolyl

3-3H-benz[e]indolyl

7-3H-benztelindolyl

2-benz[cd]indolyl

5-benz[cd]indolyl

2-1-benzonhiophenyl

5-1-benzonhiophenyl

1-2-benzonhiophenyl

7-2-benzonhiophenyl

5-1H-tetrazolyl

1-1H-tetrazolyl

5-2H-tetrazolyl

2-quinazolinyl

6-quinazolinyl

2-thiazolo[4,5-b]pyridinyl

6-thiazolo[4,5-b]pyridinyl

7-thiazolo[5,4-b]pyridinyl

4-thiazolo[4,5-c]pyridinyl

6-thiazolo[4,5-c]pyridinyl

3-5H-thiazolo[3,2-a]pyridinyl

8-5H-thiazolo[3,2-a]pyridinyl

2-7H-thiazolo[3,2-a]pyridinyl

7-7H-thiazolo[3,2-a]pyridinyl

3-3H-thiazolo[3,4-a]pyridinyl

5-3H-thiazolo[3,4-a]pyridinyl

10-10H-pyridazino[3,2-b]quinazolinyl

4-10H-pyridazino[3,2-b]quinazolinyl

8-10H-pyridazino[3,2-b]quinazolinyl

3-3H-1,2-benzodioxolyl

5-3H-1,2-benzodioxolyl

2-1,3-benzodioxolyl

7-1,2-benzodioxolyl

2-1,4-benzodioxinyl

6-1,4-benzodioxinyl

Linking X groups, besides the alkyl, alkenyl and alkynyl groups, includethe following, for example. The groups are named as they appear in thegeneric formula, but it will be understood that the groups may, in fact,be oriented in either direction.

acetylthio

sulfinyl

sulfonyl

oxycarbonyl

propoxycarbonyl

methylthiocarbonyl

butyrylamino

propionyloxy

ethylaminocarbonyl

carbonyl

oxy

thio

methoxy

propylthio

a bond

oxysulfonyl

The cyclic R⁵ groups may be substituted with a variety of substituentgroups, as set out in general in formula I. To assure that the readerfully understands the nature of those substituent groups, arepresentative group of them will be named as follows:

chloro

bromo

fluoro

trifluoromethyl

methyl

isopropyl

s-butyl

trifluoromethoxy

hydroxy

methoxy

isopropoxy

nitro

methylthio

ethylthio

formyl

acetyl

propionyl

pentanoyl

2,2-dimethylbutyryl

phenyl

oxo

phenoxy

phenylthio

methylsulfinyl

propylsulfinyl

ethylsulfonyl

isopropylsulfonyl

cyano

amino

methylamino

propylamino

diphenylmethylamino

triphenylmethylamino

benzyloxy

benzylthio

3-chlorobenzyloxy

4-fluorobenzylthio

2-nitrobenzyloxy

3-trifluoromethylbenzylthio

dimethylamino

diethylamino

di(isopropyl)amino

bis(cyclopropyl)amino

bis(cyclohexyl)amino

methyl(cyclohexyl)amino

bis(cyclohexylmethyl)amino

propyl(cyclopentylethyl)amino

cyclopentyl(cyclopropylpropyl)amino

3-methylphenyl

2-propylphenoxy

4-ethylphenylthio

3-isopropylphenylsulfonyl

4-methoxyphenyl

2-ethoxyphenoxysulfonyl

3-ethoxyphenylthio

4-chlorophenyl

4-bromophenylthio

3-fluorophenoxysulfonyl

acetylamino

propionylamino

pentanoylamino

2-ethylpropionylamino

benzoylamino

diphenylmethylaminomethyl

3-(diphenylmethylamino)propyl

aminocarbonyl

methylaminocarbonyl

isopropylaminocarbonyl

dimethylaminocarbonyl

ethyl(isopropyl)aminocarbonyl

chloroacetyl

3-bromopropionyl

4,4,4-trifluorobutyryl

3-chloro-2-methylbutyryl

3,4-dichlorohexanoyl

aminosulfonyl

methylaminosulfonyl

isopropylaminosulfonyl

diethylaminosulfonyl

methyl(propyl)aminosulfonyl

phenoxymethyl

2-phenylthioethyl

2-phenoxypropyl

3-chlorophenylthiomethyl

2-(3,4-difluorophenoxy)ethyl

2-(2-methoxy-4-propylphenoxy)ethyl

3-(3,5-diethoxlzphenoxy)propyl

3-(4-chloro-3-ethoxyphenylthio)propyl

2,6-dichloro-4-propylphenylthiomethyl

benzoyl

aminomethyl

2-aminoisopropyl

methylaminomethyl

2-ethylaminoethyl

3-(ethylamino)propyl

dimethylaminomethyl

ethyl(isopropyl)aminomethyl

3-(ethyl(propyl)amino)propyl

morpholinylinethyl

2-morpholinylpropyl

3-phenylmethyl-1-piperidinyl

4-(2-phenylpropyl)-1-piperidinyl

2-phenylmethyl-1-piperidinylaminocarbonyl

4-(3-phenylpropyl)-1-piperidinylaminocarbonyl

3-acetylamino-5-thiophenyl

2-hexanoylamino-4-thiophenyl

3-butyrylamino-4-thiophenyl

8-amino-2-naphthalenylsulfonylamino

2-methylamino-1-napththalenylsulfonylamino

5-isopropylamino-2-naphthalenylsulfonylamino

4-dimethylamino-2-naphthalenylsulfonylamino

3-methyl(propyl)amino-1-naphthalenylsulfonylamino

perfluorophenyl

perbromophenyl

While all of the compounds described by formula I are important in theconcept of the present invention, certain groups of those compoundsconstitute preferred aspects of the invention. The following table setsout a number of such preferred groups of the compounds wherein (R⁶)_(m)is absent, the use of each of which constitutes a preferred aspect ofthe invention. It will be understood that the reader can combine groupsof preferred aspects listed in the following table to produce additionalmore limited or more comprehensive preferred aspects.

a) R and R¹ both represent hydrogen;

b) R³ represents methyl;

c) R² represents C₁ -C₃ alkyl;

d) R² represents C₁ -C₂ alkyl;

e) R² represents methyl;

f) R² represents methyl or hydrogen;

g) R⁴ represents hydrogen;

h) R⁴ represents hydrogen, halo or methyl;

i) X represents alkyl, alkenyl or alkynyl;

j) X represents a bond;

k) X represents a bond or a sulfur atom;

l) X represents --SO--, --SO₂ --, or --SO₃ --;

m) X represents --CO-- or --CO--Y-- (CH₂)_(n) --;

n) X represents --Z--(CH₂)_(n) --, alkyl or --CO--;

o) X represents a bond, --Z--(CH₂)_(n) --, alkyl or --CO--;

p) X represents a sulfur atom;

q) Y represents --O-- or --S--;

r) Y represents --NH--;

s) n represents 0 or 1;

t) n represents 2 or 3;

u) n represents 0;

v) Z represents --S--;

w) R⁵ represents phenyl or naphthalenyl;

x) R⁵ represents pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl;

y) R⁵ represents anthracenyl, phenanthrenyl, fluorenyl oracenaphthalenyl;

z) R⁵ represents thiazolyl, thiophenyl or tetrazolyl;

aa) R⁵ represents benzimidazolyl, indanyl, indolyl or indazolyl;

ab) R⁵ represents quinolinyl, isoquinolinyl, quinoxalinyl orquinazolinyl;

ac) R⁵ represents benzopyranyl, benzothiazolyl, benzothiophenyl orbenzisothiazolyl;

ad) R⁵ represents benzothiazolyl;

ae) R⁵ represents benzoxazolyl, benzodioxolyl, or benzodioxinyl;

af) R⁵ represents benzisoquinolyl, benzindolyl, naphthothiazolyl,thiazolopyridinyl or pyridazinoquinazolinyl;

ag) R⁵ represents diphenylmethyl or triphenylmethyl.

Further preferred classes of compounds are also important in thepractice of the present invention. A particularly preferred class ofcompounds includes those wherein R² represents methyl or hydrogen,particularly methyl; X represents a bond, a methylthio group, a sulfuratom, or an ethyl or ethenyl group, particularly a bond or a sulfuratom; R⁵ represents phenyl, naphthalenyl, isoquinolinyl, indolyl,benzothiazolyl, pyridinyl, indazolyl, thiazolonaphthalenyl, quinolinylor diphenylmethyl; and the R⁵ group is unsubstituted or substituted with1-3, particularly 1, groups chosen from the group consisting of halo,trifluoromethoxy, trifluoroethoxy, trifluoromethyl, C₁ -C₃ alkyl,methoxy, nitro, phenyl, toluenesulfonyl, and pivaloylamino.

A further preferred class of compounds of the present invention includesthose described in the paragraph immediately above, and, in addition,those wherein X represents propyl, aminocarbonylmethyl, methoxycarbonyland oxycarbonyl; R⁵ represents thiophenyl, fluorenyl, indanyl,quinoxalinyl, pyridazinyl, thiazolopyridinyl, and benzisoquinolinyl; andthe R⁵ group is unsubstituted or substituted with 1-3, particularly 1,groups chosen from the group consisting of hydroxy, C₁ -C₄ alkyl, oxo,benzyloxy, phenoxymethyl and benzylpiperidinyl.

As described in formula I, the invention includes pharmaceuticallyacceptable salts of the compounds defined by the above formula. Althoughgenerally neutral, a particular compound of this invention can possess asufficiently acidic, a sufficiently basic, or both functional groups,and accordingly reach with any of a number of nontoxic inorganic bases,and nontoxic inorganic and organic acids, to form a pharmaceuticallyacceptable salt. Acids commonly employed to form acid addition salts areinorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodicacid, sulfuric acid, phosphoric acid, and the like, and organic acidssuch as p-toluenesulfonic, methanesulfonic acid, oxalic acid,p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid, and the like. Examples of suchpharmaceutically acceptable salts thus are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, gamma-hydroxybutyrate, glycollate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, mandelate, and the like. Preferredpharmaceutically acceptable acid addition salts are those formed withmineral acids such as hydrochloric acid and hydrobromic acid, and thoseformed with organic acids such as maleic acid and methanesulfonic acid.

Base addition salts include those derived from nontoxic inorganic bases,such as ammonium or alkali or alkaline earth metal hydroxides,carbonates, bicarbonates, and the like. Such bases useful in preparingthe salts of this invention thus include sodium hydroxide, potassiumhydroxide, ammonium hydroxide, potassium carbonate. The potassium andsodium salt forms are particularly preferred.

Thus, the groups R⁴ and X--R⁵ include a number of substitutions each ofwhich may be placed at the 7, 8 or 9-position of the nucleus of formulaI. All such substituents are easily understandable by the chemist, but anumber of the contemplated substituent arrangements will be mentionedfor the convenience of the reader.

8-(6-phenoxysulfonyl-4-quinolinyloxy)7-chloro-8-(3-chloromethyl-7-quinolinylthio)7-[2-(3-phenoxy-6-isoquinolinylaminocarbonyl)ethyl]

9-fluoro-7-(1-methoxycarbonyl-4-isoquino-linylmethyl)8-[3-(5-bromo-t-butyl-3-quinoxalinyl)propyl]

8-fluoro-7-[3-(8-butylthio-2-quinoxalinyl)-3-propynyl]7-(3-phenyl-1,2-benzisothiazol-5-yloxycarbonyl)

8-bromo-9-(5-hexyloxysulfonylbenzoxazol-2-ylthio)

9-methyl-7-(6-trifluoromethyl-2,1-benzisothiazol-3-yl)

7-(3-isopropoxycarbonylaminopyridinyl-2-ylmethyl)9-chloro-8-(7-hydroxy-4-benzothiazolylthio)7-(4-isopentoxycarbonyl-1H-indazol-4-yloxy)

7-ethyl-9-[3-(6-[2-ethyl-5-methylphenoxysulfonyl]-1H-indazol-3-yl)-2-propynyl] 9-[2-(6-ethoxycarbonyl-2H-indazol-2-yloxy)ethyl]8-[2-(3-fluoro-2H-indazol-6-yl)ethoxy]

9-chloro-7-(3-trifluoromethoxy-3H-indazol-4-yl-thiocarbonylmethyl)

7-[2-(5-propoxy-4-[4-fluorophenoxy]-3H-indazol-7-ylthio)ethyl]

8-ethyl-7-[4-(4-[3-chlorophenoxysulfonyl]-2-indolyl)butyl]

8-[3-(7-methoxy-4-[2,3-dichloropropoxycarbonyl-amino]2-indolyloxy]propyl

7-[2-(5-[4-fluoro-3-methylphenoxysulfonyl]-2H-indol-4-yl)ethylcarbonylthio]

8-methyl-7-[3-(6-chloro-2-[3-chloro-5-ethylphenoxyethyl]-2H-indol-3-yl)-2-butynyl]

Synthesis

The synthesis of the compounds wherein R⁴ and X--R⁵ are absent isclearly explained with numerous examples in U.S. Pat. No. 5,239,075, andthe reader is referred thereto.

Synthesis of the compounds of formula I wherein (R⁶)_(m) is absent mayproceed in various ways, depending in large part on the identity of thegroup --X--R⁵. It is very often advantageous to form thebenzo[f]quinoline nucleus without the --X--R⁵ group, and to add thatgroup in a separate step, thus providing a convergent synthesis. In sucha case, the --X--R⁵ group of the compound of formula I is replaced by aleaving group, preferably a bromine atom, when the benzo[f]quinolinenucleus is prepared. Since the R⁴ group of the nucleus is small, it maybe in place throughout the synthesis. Thus, an important intermediate isthe following compound of formula II. ##STR3##

wherein L represents a leaving group, preferably bromo.

Synthesis of Nucleus

A series of synthetic methods for the preparation of intermediates offormula II was taught by Audia et al. in U.S. Pat. No. 5,239,075, issuedAug. 24, 1993. That patent is incorporated by reference herein, and thereader readily will understand the synthetic methods taught by it.

A preferred method for preparing the intermediates of formula II wherein(R⁶)_(m) is absent is the heteroannulation carried out by reacting anenamine of the formula ##STR4## with an activated acrylate, particularlyacryloyl chloride, acrylic anhydride, or acryloyl toluenesulfonate ormethanesulfonate. The group R⁸ in the above intermediate is a chiraldirecting group, in order to obtain the correct enantiomer of theintermediate of formula II. The most preferred R⁸ group is(R)-(+)-1-phenylethyl. This process is taught in general by EPOPublication 0564193.

The product of the heteroannulation just described is of the formula##STR5## and the double bond at the 4a,5- position must be reduced in asecond step. The reduction is readily carried out under mild conditionswith chemical reducing agents such as borohydrides. Cyanoborohydride ispreferred; the reduction may be carried out, for example, in formic acidunder ambient conditions. More conveniently, the reduction step may becombined with the removal of the R⁸ group, by reaction withtrifluoroacetic acid in a reaction medium containing or consisting oftriethylsilane at reduced temperature in the range of from about -40° to0°.

The above heteroannulation is carried out under mild process conditions.In most instances it will be found that excellent yields are obtained inshort periods of time at temperatures in the range of ambient. Forexample, temperatures from about 0° to about 150° are used, and reactiontimes in the range from a few minutes to a few hours are sufficient.Preferable reaction temperatures are in the range from about -20° toabout ambient temperature, and most preferably the reactants arecombined at very low temperatures in the range of -20° to -80°, and thereaction mixture is allowed to warm slowly to ambient temperature whilethe reaction occurs. The reaction mixture may be a biphasic mixture of aconvenient organic solvent and an aqueous solution of a mild base. Forexample, solvents may include haloalkanes, ethers, includingtetrahydrofuran, and nitriles including acetonitrile. Preferred mildbases are alkali metal carbonates and bicarbonates; more highly basicreagents, such as alkali and alkaline earth metal hydroxides and thelike may be used, but the bicarbonates are usually preferred.

One-Pot Nucleus Process

A particularly preferred method of synthesis of a key intermediate offormula II proceeds according to the following scheme.

An intermediate of the formula ##STR6## wherein L is bromo, and islocated at the 7-, 8- or 9-position is prepared by reacting a compoundof the formula ##STR7## with methyl iodide in an ether solvent toprepare a compound of the formula ##STR8## combining acrylic anhydrideor acryloyl chloride with the reaction mixture comprising the compoundof formula VII to prepare a compound of the formula ##STR9## quenchingthe reaction with sodium bicarbonate, evaporating the organic solutioncomprising the compound of formula VIII; and combining the residuecomprising the compound of formula VIII with a trialkylsilane andtrifluoroacetic acid in the absence of a solvent to prepare the compoundof formula V.

The starting material of formula VI is prepared most conveniently by amodification of a process shown in European Patent Publication 0564193.A substituted 2-tetralone, having the desired L substituent on theunsaturated ring, is reacted with (R)-(+)-phenethylamine to prepare theintermediate of the formula ##STR10## The reaction is convenientlycarried out at elevated temperature, particularly the refluxtemperature, in toluene in the presence of a strong acid such asp-toluenesulfonic acid. Water must be removed as it is formed in thisreaction, and the absence of water being formed is an indication ofcompletion of the reaction. A slight excess of phenethylamine, such asabout 1.05-1.10 equivalents, should be used. Alternatively,tetrahydrofuran (THF) may be used as the solvent, and it is particularlyconvenient in that case to use molecular sieves to dehydrate thereaction mixture, using at least twice the weight of molecular sievescompared to the amount of water which will be released by the process.

The above phenethylamino compound is lithiated to prepare the startingmaterial of formula VI. The reaction may be carried out with, forexample, n-butyllithium or with lithium diisopropylamide (LDA). When thereaction is carried out, as is preferred, with LDA, the best results areobtained if the LDA is freshly generated from diisopropylamine andn-butyllithium immediately before use in the process. A substantialexcess, about 15-25%, of LDA should be used for best results.

The LDA reaction is best carried out in THP at a low temperature in therange of about -100° to about 0°, preferably about -78° to about -10°.The phenethylamino compound need not be purified or isolated, but thefirst reaction mixture should be evaporated under vacuum and the residuetaken up in THP. It is preferred to add the phenethylamino material, insolution, to a solution of LDA in cold tetrahydrofuran; the oppositemanner of addition is operable but provides lower yields. The reactionmay be carried out in quite short periods of time, less than one hour ingeneral.

The lithio compound of formula VI is difficult to isolate and purify,and so it should be introduced into the process as a solution in thelithiation reaction mixture.

In the first step of the present process, the lithio compound of formulaVI is reacted with methyl iodide to provide the compound of formula VII.It is advisable to use about 15-25% of excess methyl iodide, and tocarry out the process in an ether solvent, such as diethyl ether, methylbutyl ether or, preferably, THF. The reaction is very rapid at lowtemperatures in the range of about -100° to about -50°, most preferably,about -80° to about -60°. Reaction times in the range of from about afew minutes to about one hour are adequate, and a 20-minute reactiontime is often preferred.

If the compound of formula VI is in the form of the reaction mixturefrom lithiation with LDA, and the reaction mixture therefore containsthe residual diisopropylamine, that amine must be neutralized beforefurther reaction of the compound of formula VII. Most conveniently, themethyl iodide mixture is allowed to warm to a temperature close to 0°,and a sufficient amount of methanesulfonic acid is added to neutralizethe diisopropylamine. Other strong acids may be used, butmethanesulfonic acid is particularly convenient because the resultingmethanesulfonate salt of diisopropyl-amine is only slightly soluble andtherefore may be easily removed by simple filtration or centrifugation.

The reaction mixture comprising the compound of formula VII is combinedwith acrylic anhydride or acryloyl chloride to initiate theaza-annulation reaction which forms the compound of formula VIII. It isbest to generate the acrylic anhydride, the preferred reagent,immediately before use by the reaction of acryloyl chloride and acrylicacid, using triethylamine and a stabilizer, such as hydroquinone andbutylated hydroxytoluene, in THF.

The aza-annulation is best carried out by adding the acrylic anhydrideor acryloyl chloride at a very low temperature, such as from about -100°to about -70°, and allowing the mixture to warm very slowly withstirring to a temperature in the range of about -20° to about 0°, oreven up to about 10°-20°. A period of 12-15 hours is not too much forthat period of time. When the reaction has gone as far toward completionas is desired, the reaction is quenched by addition of sodiumbicarbonate. It is preferred to use from about 1.5 to about 4equivalents of base, most preferably about 2 equivalents. The base maybe added as a solution, for example, in water or in an aqueous solventsuch as water/dimethylaminopyridine, but it is preferred to add the basein solid form. The reaction mixture is stirred with the quenching basefor a brief period, and then the mixture is filtered, the volatiles areremoved, and the solvent may be replaced with an ether solvent,preferably diethyl ether, and the organic solution may then be worked upby washing with aqueous base and aqueous acid, and perhaps withadditional purification steps such as a wash with a saturated saltsolution. If such work up steps are used, the solution is thendehydrated and evaporated under vacuum to obtain the non-volatileportions of the reaction mixture, containing the final intermediate offormula VIII. On the other hand, the residue from the quenched reactionmixture may be carried on without work up if desired.

The residue from the aza-annulation step is cooled, and a chilledmixture of a trialkylsilane and trifluoroacetic acid is added. Theaddition should take place at a low temperature in the range of fromabout -40° to about 0°, and no other solvent is used. A large quantityof trifluoroacetic acid, in the range of about 10-50 equivalents, mostpreferably about 20-30 equivalents is used. The preferred trialkylsilaneis triethylsilane, although trimethylsilane, tripropylsilane and thelike may also be used. A substantial excess of trialkylsilane, in therange of about 5-20 equivalents, most preferably about 7-15 equivalentsis used. The mixture is stirred for about 10-20 hours while it isallowed to warm slowly to about 30°, and then the mixture is slowlyheated to an elevated temperature, preferably the reflux temperature,and is stirred at that temperature for a few hours, such as about 2-6hours to complete the formation of the compound of formula V.

The residue containing the intermediate of formula V is dissolved,preferably in a haloalkane such as dichloromethane, washed with base,such as aqueous sodium bicarbonate, and concentrated under vacuum. Theresidue is thoroughly washed with, for example, an ether solvent whichmay often preferably be diethyl ether to obtain the purified desiredcompound of formula V.

Further details of the process will be shown below as Preparations.

It will be understood that the principles of the above process may beapplied to compounds of the present invention other than the specificintermediates shown. So long as the R⁴ and X--R⁵ substituents, or the(R⁶)_(m) substitutents, of the compound to be prepared are stable underthe reaction conditions, particularly the exposure to LDA, thosesubstituents may be placed on the starting tetralone and carried throughthe steps of the process to prepare the complete compound of formula Iin a single linked process, although the one-pot aspect of the aboveprocess may not be possible with such starting materials.

Alkylation Process

It is necessary in the synthesis to alkylate the nucleus to add the R²substituent, if one is desired. U.S. Pat. No. 5,239,075 shows suchalkylation by reaction with an alkyl iodide in the presence of a verystrong base such as sodium hydride, a conventional process step. Similaralkylations are shown below in the presence of, preferably, potassiumt-butoxide in t-butanol as solvent.

The present invention also provides a superior and preferred process foralkylating certain benzoquinolinone compounds which include many of thecompounds of the present invention, and also many of the compoundspreviously disclosed in U.S. Pat. No. 5,239,075. The process allowsparticularly economical and ready alkylation of the N-4 position of themolecule without the necessity to use unusually strong bases such aspotassium t-butoxide and the like. The compounds which are prepared bythe present alkylation process are of the formula ##STR11## whereinR^(2') is methyl, ethyl or n-propyl;

R^(3') is hydrogen or methyl;

R⁴ is hydrogen, halo, methyl or ethyl;

R^(5') is halo, nitro, cyano, C₁ -C₆ alkyl, trifluoromethyl or C₁ -C₆alkoxy; or R^(5') is a group --A--R⁷ wherein A is C₁ -C₆ alkyl, C₂ -C₆alkenyl, or C₂ -C₆ alkynyl; and R⁷ is halo, trifluoromethyl, or C₁ -C₆alkoxy;

or R^(5') is a group --X'--R⁹ wherein X' is C₁ -C₄ alkyl, C₂ -C₄alkenyl, C₂ -C₄ alkynyl or a bond;

and R⁹ is phenyl, naphthalenyl, pyridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, anthracenyl, acenaphthalenyl, thiazolyl, benzimidazolyl,indazolyl, thiophenyl, phenanthrenyl, quinolinyl, fluorenyl,isoquinolinyl, indanyl, benzopyranyl, indolyl, benzisoquinolinyl,benzindolyl, benzothiazolyl, benzothiophenyl, quinoxalinyl,benzoxazolyl, tetrazolyl, naphthothiazolyl, quinazolinyl,thiazolopyridinyl, pyridazinoquinazolinyl, benzisothiazolyl,benzodioxolyl, benzodioxinyl, diphenylmethyl or triphenylmethyl;

the above R⁹ groups are unsubstituted or substituted with 1-3 groupschosen from the group consisting of halo, trifluoromethyl,trifluoroethoxy, C₁ -C₄ alkyl, trifluoromethoxy, hydroxy, C₁ -C₃ alkoxy,nitro, C₁ -C₃ alkylthio, C₁ -C₆ alkanoyl, phenyl, oxy, phenoxy,phenylthio, C₁ -C₃ alkylsulfonyl, cyano, benzyloxy, benzylthio,(mono-halo, nitro or trifluoromethyl)benzyl(oxy or thio), (mono-C₁ -C₃alkyl, C₁ -C₃ alkoxy or halo)-(phenyl, phenoxy, phenylthio,phenylsulfonyl or phenoxysulfonyl), halo-C₁ -C₆ alkanoyl, phenyl(oxy orthio)(C₁ -C₃ alkyl), (halo, C₁ -C₃ alkyl or C₁ -C₃ alkoxy)phenyl(oxy orthio) (C₁ -C₃ alkyl), or benzoyl;

or an above R⁹ group is substituted with a morpholino (C₁ -C₃ alkyl)group, or a phenyl (C₁ -C₃ alkyl) piperidinyl group;

or R⁹ is a perhalophenyl group; the process comprises reacting acompound of the formula ##STR12## with methyl, ethyl or n-propyl iodidein a reaction mixture comprising an organic solvent chosen from thegroup consisting of tetrahydrofuran, dimethoxyethane, diethoxyethane andmethyl t-butyl ether, and aqueous sodium or potassium hydroxide.

The compounds prepared by the alkylation process are among those whichhave been described in full above, or have been described in full in theabove-mentioned patent. No additional description of the products isnecessary. Similarly, the starting materials of Formula B have also beenthoroughly described, and they are prepared by the general methods ofpreparation described in this document or in U.S. Pat. No. 5,239,075.

The present process itself is readily carried out, and is distinguishedby both particularly effective alkylation, under mild and easilycontrolled conditions, and by particularly easy isolation of theproducts. Frequently, prior art alkylations of similar types requiredthe use of phase transfer catalysts to isolate the products insatisfactory yield and purity, but it has been found that the productsof the present alkylations are isolated by simple crystallization.

Certain aspects of the alkylation process are preferred and will bementioned below specifically. It will be understood that the followingaspects are each important individually, and also that preferred aspectsmay be combined to create further, more limited or more expansive,preferred aspects.

a) R^(2') is methyl and the compound of formula B is reacted with methyliodide;

b) R^(2') is methyl or ethyl and the compound of formula B is reactedwith methyl or ethyl iodide;

c) R^(3') is hydrogen;

d) R^(3') is methyl;

e) R⁴ is hydrogen;

f) R^(5') is halo;

g) the organic solvent is tetrahydrofuran;

h) the hydroxide is sodium hydroxide;

i) the concentration of the aqueous sodium or potassium hydroxide isnear saturation.

The alkylation process is carried out in conventional chemical plantequipment, preferably at ambient pressure and at moderate temperatures.It is preferably begun by slurrying the starting material of formula Bin the organic solvent at a temperature near ambient, such as from about0° to about 50°, more preferably from about 15° to about 25°. The mostpreferred organic solvent is tetrahydrofuran (THF), and it is preferredto use about 5-15 liters of solvent per kilogram of starting material;more preferable solvent volume is about 10 liters per kilogram. Thealkyl iodide is then added as neat liquid. A substantial excess of alkyliodide is preferably used, such as about 1.2-1.8 equivalents based onthe starting material, most preferably about 1.5 equivalents.

The aqueous sodium or potassium hydroxide is then added, still at aboutambient temperature, in an amount of about 1-4 liters per kilogram ofstarting material. The quantity of aqueous base is somewhat dependent onthe concentration of the base and the choice of sodium or potassiumhydroxide; when the most preferred base, 50% sodium hydroxide, is used,the most preferred amount of it is about 2 liters per kilogram ofstarting material. Then the reaction mixture, consisting of solidmaterial slurried in two liquid phases, is warmed to about 25°-65° withvigorous agitation and the reaction is allowed to proceed at aboutconstant temperature with constant agitation. The preferred reactiontemperature is about 35°-40°. As the reaction proceeds towardcompletion, the solid starting material and alkyl iodide will dissolveand react, so the disappearance of solids is a crude indication ofcompletion. The reaction may be followed by high pressure liquidchromatography (HPLC) on C-18 silica gel column, eluting with 1:1acetonitrile:aqueous buffer (5% ammonium acetate and monitoring at 220nanometers.

When the reaction has gone as far as is desired toward completion, themixture is cooled to about ambient and the aqueous layer is separatedand discarded.

The preferred purification and isolation procedure proceeds by dilutingthe organic layer with water, and neutralizing it with aqueous mineralacid. Then the solution is distilled until the vapor temperature risesto about 69°-80°, removing most of the THF. Slow cooling to about 5°over a period of about 1-14 hours crystallizes the product, which needsonly washing with water and drying to be ready for use as anintermediate or as a pharmaceutical.

The alkylation process provides product in the same stereochemical formas the starting material, in satisfactory purity for the pharmaceuticalindustry, and in yields of or above 90% when operated according to thepreferred manners.

The following Examples further explain the process and provide detailswhich will be of use to the skilled reader.

EXAMPLE 1(4aR)-(10bR)-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

To a 1-liter flask equipped with a condenser and a stirrer were added470 mL of THF, 18.7 g of methyl iodide and 47 g of(4aR)-(10bR)-8-chloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one, and stirring was begun at ambient temperature. To themixture was added 100 ml of 50% aqueous sodium hydroxide in one portion,and gentle heating was begun. The temperature was raised as high as 41°and was then gradually lowered to 29° at the end of 16 hours ofstirring. HPLC liquid chromatography, eluting with 1:1acetonitrile:aqueous buffer (5% ammonium acetate) and monitoring at 220nanometers, then showed that all the starting material had been consumedand the aqueous layer was removed. The organic layer was concentrated toan oil under vacuum, and the residue was dissolved in ethyl acetate. Thesolution was washed with brine, and the organic layer was washed with200 mL of water twice, and was dried over magnesium sulfate andevaporated under vacuum while heptane was added portionwise as the ethylacetate was removed. A total of 500 mL of heptane was added, and theproduct began to crystallize when about half of it had been added. Theslurry was concentrated to about 300 ml, and filtered, and the solidswere washed with heptane and dried in vacuum at 40°-50° to obtain 47.03g of product, m.p. 97°-99°, of 98.7% purity.

The following example shows an advantageous manner of isolating theproduct of the present alkylation.

EXAMPLE 1A(4aR)-(10bR)-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

Two hundred L of THF was added to a reactor, and 24.6 kg of(4aR)-(10bR)-8-chloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onewas added. Then 35 kg of methyl iodide was added, rinsed in with 10 L ofTHF. A 79.6 kg portion of 50% aqueous sodium hydroxide was added in 13minutes at 15°-25°, rinsed in with 40 L of THF. The mixture was stirredat 36°-39° for 13 hours, and was then cooled to 15°-25°. The layers wereallowed to separate, and the water/THF phase was neutralized to pH 7with hydrochloric acid and heated to reflux. Distillate was removeduntil the temperature reached 77°. A total of 154 kg of water was addedfrom time to time. The solution was cooled over 3 hours to 3°-10°, andwas then stirred vigorously at that temperature until solids began toform. Then the slurry was stirred gently at constant temperature for 3hours. The slurry was filtered, and the vessel and filter cake werewashed with cold water. The cake was air dried at 25°-35° for 75 hoursno obtain 27.3 kg of the desired product, potency 85.1% by liquidchromatographic analysis.

EXAMPLE 2(4aR)-(10bR)-8-chloro-4-ethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 9.4 g portion of(4aR)-(10bR)-8-chloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onewas combined in a flask with 94 ml of THF, 20 mL of 50% aqueous sodiumhydroxide and 9.36 g of ethyl iodide, and was stirred at reflux, about66°, for about 16 hours. The mixture was cooled to ambient temperature,and the layers were separated. The organic layer was evaporated to anoil, which was dissolved in ethyl acetate and extracted three times with100 mL portions of water. It was then dried and evaporated to half itsvolume while heptane was added in portions. The resulting whitecrystalline product was filtered, washed with heptane and dried undervacuum at 25° to obtain 3.15 g of the desired product, m.p. 108°-110°.Analysis calculated for C₁₅ H₁₈ ClNO: C, 68.54; H, 6.83; N, 5.54 Found:C, 68.50; H, 6.88; N, 5.31 Mass spec. (f.d.): M+263

EXAMPLE 3(4aR)-(10bR)-8-chloro-4-ethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 9.4 g portion of(4aR)-(10bR)-8-chloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onewas combined with 150 mL of THF, 20 mL of 50% aqueous sodium hydroxideand 12.5 g of ethyl iodide in a flask, and was warmed with stirring toabout 37°. Stirring at approximately constant temperature was continuedfor about 72 hours and the reaction was worked up as described above inExample 2 to obtain 3.88 g of the desired product, m.p. 108°-110°. Theproduct was found to be 98.6% pure by HPLC, eluting with 1:1acetonitrile:aqueous buffer (5% ammonium acetate) and monitoring at 220nanometers.

EXAMPLE 4(4aR)-(10bR)-8-chloro-4-propyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 2.35 g portion of(4aR)-(10bR)-8-chloro-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onewas slurried in 40 mL of THF and 5 mL of 50% aqueous sodium hydroxide,and 3.4 g of propyl iodide was added. The mixture was heated to about60°, and the mixture was stirred at that temperature for about 22 hours.Workup was carried out by separating the organic layer and evaporatingit to dryness, and adding water and ethyl acetate. The organic layer wasseparated, washed twice with water, dried, filtered and evaporated undervacuum to obtain 710 mg of white crystalline product, found to be ofabout 90% purity. It was then purified by silica gel flashchromatography, eluting with ethyl acetate, to obtain 510 mg of purifiedproduct, m.p. 110°-11°, of 98.98% purity, by HPLC, eluting with 1:1acetonitrile:aqueous buffer (5% ammonium acetate) and monitoring at 220nanometers. Analysis calculated for C₁₆ H₂₀ NClO: C, 69,18; H, 7.26; N,5.04 Found: C, 68.92; H, 7.09; N, 5.15

If a product of formula I having an isopropyl R² group is desired,alkylation of the intermediate of formula VIII may be accomplished withisopropyl iodide, using sodium hydride as an activating agent andoperating the reaction in a solvent of the group mentioned just above atan elevated temperature such as the reflux temperature.

Frequently a final stage intermediate such as that of formula VIII isproduced in a racemic form as a mixture of the two trans-4a-10b isomers.Such an isomeric mixture may be converted to substantially pure desiredenantiomers by a process clearly explained in U.S. Pat. No. 5,239,075,which proceeds by opening the piperidinone ring with a strong acid suchas methanesulfonic acid, preparing a chiral salt with(-)-(R,R)-di-p-toluyltartaric acid, and separating the desiredenantiomeric form of the salt as typically is done in such resolutions.The salt is then sprung with aqueous base and the piperidinone ring isreclosed by simple heating.

Oxidation

Another operation which may be carried out on the nucleus of thecompounds of the present invention is oxidation to provide the compoundswherein R and R¹ represent a bond. Such oxidations are convenientlycarried out by reaction with an oxidizing agent such as2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in the presence ofbis(trimethylsilyl) trifluoromethyl acetamide, preferably in dioxane assolvent. The oxidations are carried out at elevated temperature, such asthe reflux temperature or from about 50° to about 150°, and preferablythe reaction mixtures are stirred at about ambient temperature for aperiod of time before heating is begun. Further, information about suchoxidations can be found below in the Examples.

Leaving Groups

In the course of preparing compounds having various X--R⁵ groups, it isnecessary or convenient to provide nucleus compounds havingcorresponding leaving groups or reactive groups. For example, compoundshaving carboxy, thio, hydroxy, amino, formyl and B(OH)₂ groups areneeded for various syntheses and are readily prepared, as isdemonstrated below, for example, in the Preparations. Such compounds arepreferably prepared from compounds having a halogen atom, particularly abromine atom but also iodine atom on the nucleus.

(X--R⁵ Groups)

Various processes are conveniently used for placing the X--R⁵ groups onthe benzoquinolinone nucleus; the choice of processes is primarilydependent on the nature of the x group. Where the X group is merely abond, a preferred process is dependent on palladium mediated boronchemistry. In one preferred process, a benzoquinolinone nucleus compoundhaving a bromine atom as the L substituent is reacted with anintermediate which constitutes the R⁵ substituent group with a boronicacid (B(OH)₂) at the point of attachment to the benzoquinolinonenucleus. The reaction is conveniently carried out in the presence of acatalytic amount of tetrakis triphenylphosphine) palladium, in a basicreaction mixture including, for example, aqueous sodium carbonate ortriethylamine. The preferred solvent is an ether such as THF ordimethoxyethane (DME), and the reactions go cleanly at elevatedtemperatures such as the reflux temperature or from about 50° to about100°. A useful variation on the above process is carried out using anester of boronic acid as the intermediate, such as a diethylborane. Theexamples show illustrations of such syntheses.

Similarly, compounds having a bond as the X group may be synthesized bythe palladium mediated reaction of a bromine-substituted compoundproviding the R⁵ group with a boronic acid-substituted benzoquinolinonenucleus.

Still another method for preparing compounds having no X group is toreact a halo-substituted nucleus compound of formula IV with a compoundcomprising the desired R⁵ group, substituted with a tri-n-butylstannylgroup at the point of attachment. Such reactions are carried out in thepresence of a small amount of bis(triphenylphosphine)palladium halide athigh temperatures such as from about 60° to about 120°. A solvent suchas acetonitrile may be used, and the reaction should be carried out ininert gas atmosphere.

Another particularly important group of compounds of formula I are thosewherein X is a sulfur atom. Such groups are conveniently prepared by atleast two main processes. In one process, a halo-substitutedbenzoquinolinone nucleus compound is reacted with a disulfide of theformula R⁵ --S--S--R⁵. For example, if a benzylthio substituent is to beprovided, the disulfide would be dibenzyldisulfide. The reactions goreadily at ambient temperature after combining the reactants at a verylow temperature, such as from about -50° to about -100°, in an ethersolvent in the presence of a very strong base, particularly acombination of methyllithium and t-butyl-lithium. The reactions arerapid and may be carried out in 1 hour or, at most, a few hours. Anothermethod of synthesis of thiosubstituted compounds, which avoids the useof very low temperatures, is one where either the nucleus or thecompound providing the R⁵ group is substituted with an SH group and theother is substituted with a bromine, chlorine or iodine atom. Suchreactions are carried out at ambient or moderately elevatedtemperatures, such as from about 50° to about 100°, in a high-boilingsolvent such as dimethyl-formamide and in a basic reaction medium. Suchbases as potassium carbonate, sodium bicarbonate, triethylamine andother moderately strong bases are adequate. Numerous examples of suchsyntheses are shown below.

Similarly, when the group X is an oxygen atom, the compounds areconveniently prepared by reactions where one of the nucleus and the R⁵group--providing compound carries a halogen atom, and the other carriesa hydroxy group. As usual with such reactions, basic conditions andmoderately elevated temperatures, such as were just described, areadequate to provide reasonably prompt and clean production of thedesired compound of formula I.

Compounds wherein X is an oxyalkyl or thioalkyl group are prepared froma nucleus compound having a formyl or formylalkyl L substituent, whichmaterial is prepared, as shown below, by reaction of a halo-substitutednucleus compound with dimethylformamide in the presence of a very strongbase, to prepare the formyl substituted compound. It is reduced to forma hydroxymethyl group, which is converted to a haloalkyl group, andfinally reacted with an SH or OH-substituted compound providing the R⁵group.

The group of compounds of formula I where X is alkyl, alkenyl or alkynylare made, in general, by processes where a halo-substituted nucleuscompound is reacted with a compound providing the X--R⁵ group, in thepresence of a 9-borabicyclo [3.3.1]nonane alkyl compound (generated insitu by treatment of the appropriate alkene with9-borabicyclo[3.3.1]nonane (9-BBN)) or of abis(tri-substituted-phosphine)palladium compound, at a high temperaturein an inert atmosphere. Solvents such as dimethylformamide may be used,and a basic environment provided by triethylamine or the like isappropriate. Temperatures in the range of from about 80° to about 140°may be used for long periods of time up to as much as 24 hours. Theresulting compounds may be hydrogenated in conventional manners toreduce them from alkynes to alkenes or from alkenes to alkyls.

Another method of synthesis of alkyl-linked compounds may be carried outby reacting the halo-substituted benzoquinoline nucleus compound with avery strong base, preferably a combination of methyllithium andt-butyllithim, and then adding an aldehyde or ketone providing thedesired X--R⁵ substituent. For example, an example below shows thepreparation of a compound wherein X is a bond and R⁵ is diphenylmethylby such a reaction of benzophenone. Such reactions should be carried outat low temperature, warming to ambient or slightly elevated temperature,preferably in an ether solvent.

Compounds of formula I wherein X is a carbonyl group, an ester group ora carboxamide are prepared in manners following the general processesfor synthesis of such compounds. For example, a compound where X is acarboxamide may conveniently be prepared by reacting a halo-substitutedbenzoquinolinone nucleus compound with an isocyanate carrying thedesired R⁵ group. Such reactions are carried out in ether solvents,frequently preferably THF, in the presence ofmethyllithium/t-butyllithium at low temperatures.

Another method for synthesis of carbonyl-substituted compounds is toreact an aldehyde with a halo-substituted nucleus compound, to provide ahydroxymethyl-substituted intermediate. Such a reaction is carried outin the presence of methyllithium/t-butyllithium at low temperatures,again in an ethereal solvent by preference. The hydroxymethylintermediate is oxidized, as with Jones reagent under the usualconditions for such reactions, to prepare the desired compound where Xis a carbonyl group.

The benzoquinolinone intermediate having a carboxy substituent on thephenyl ring, the preparation of which is shown below as a Preparation,is conveniently used to prepare compounds where X incorporates an esteror amide linkage, by conventional esterification reactions withalcohols, or amide preparations with amines. All of the conventionalreaction conditions are applicable, such as the use ofcarbonyldi-imidazole as an initiator, or oxalylchloride/dimethyl-formamide. When an X group incorporates an alkylenechain together with an ester or amide linkage, appropriate startingmaterials including the alkylene chain are used as a chemist wouldanticipate.

On the other hand, when the X group comprises an amide linkage where thenitrogen is linked to the benzoquinolinone, the amino-substitutedintermediate prepared below is conveniently reacted with, for example, acarbonyl halide carrying the desired R⁵ group under the conventionalreaction conditions. Again, small alkylene groups may be incorporated asdesired to make up any of the possible X groups in the contemplation ofthe present invention.

For example, an unsaturated alkyl-substituted nucleus compound, preparedas discussed above, may be oxidatively cleaved to form the correspondingcarboxyalkyl compound. Oxidizing agents such as periodates are commonlyused for such transformation and may be used in these instances. Thecarboxy compound is then esterified or amidated in the usual manner toprepare the desired alkyl-ester or alkyl-amide X group.

It will be understood that the above discussions of esters includethioesters where the group Y represents a sulfur atom, as well as themore commonly used esters.

Finally, numerous transformations are or may be carried out on R⁵groups, to transform one compound of the present invention to anothercompound. For example, a compound where the R⁵ group is substituted witha functional group such as alkanoyl, especially formyl, may be reactedwith an amine to prepare the corresponding aminoalkyl-substitutedcompound. Compounds having, for example, nitro groups may be reduced toform the corresponding amino-substituted compounds, andamino-substituted compounds may be reacted with ketones or aldehydes inthe presence of reducing agents, or by subsequent reduction, to preparethe corresponding compounds wherein the R⁵ group is substituted withalkyl amino.

Further information about the preparation of compounds of the presentinvention is to be found in the following Preparations and Examples,which, while certainly not intended to limit the present invention, areillustrative of the processes by which all of the compounds areprepared.

The first group of Preparations below illustrate the preferred synthesisof the benzoquinolinone nucleus compounds which process was described indetail above.

PREPARATION 1 (R)-6-bromo-2-(1-phenylethylamino)-3,4-dihydronaphthalene,lithium salt

6-Bromo-2-tetralone, (45.0 g, 200 mmol uncorrected, potency of 90%, 0.90equiv, corrected) was refluxed with (R)-(+)-phenethylamine (26.6 g, 220mmol, 1.10 equiv, p-toluene-sulfonic acid (160 mg, 0.84 mmol, 0.004equiv), and toluene (600 mL) in a 2000-mL round bottom flask fitted witha water separator. Reflux was continued until a water-free distillatewas observed and then approximately 250 mL of toluene was collected overabout 2 to 3 hours. The mixture was cooled to approximately 30°-35° andconcentrated under house vacuum.

The residue above, containing the enamine intermediate, was dissolved intetrahydrofuran (THF, 480 g, 540 mL) and cooled below -50°. Thissolution of the enamine was added via cannula to a solution of lithiumdiisopropylamide (LDA, 1.15 equiv) at -50° to -60° over 5 minutes. Thesolution was warmed to -5° over 20 minutes and then recooled to -75°affording a 0.125M solution of the lithium salt starting material.Proceed immediately to next step--unstable intermediate.

PREPARATION 2(4aR)-10bR)-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneStep A--Methyl Iodide

Methyl iodide (14.4 mL, 230 mmol, 1.15 equiv.) was added via syringe tothe reaction mixture from Preparation 1 at -75° to -70° over 3 minutes.This solution was warmed to -5° in 20 minutes and then treated withmethanesulfonic acid (24.8 g, 16.8 mL, 1.3 equiv.) affording a solutionof the desired enamine admixed with diisopropylamine methanesulfonate asa slightly soluble, off-white precipitate, which was then removed byfiltration.

Step B--Aza-Annulation

The reaction mixture solution from the above step was treated withacryloyl chloride (1.7 equiv.) at -75° in one portion over about 5minutes. The mixture was then allowed to warm to -8° over 15 hours. Thereaction was quenched by pouring into sodium bicarbonate (60 g in 240 mLof water at 5° to 7°, 15 minutes addition time, 20 minutes stir, pHshould be basic). Dimethylaminopyridine (0.01 equiv, 2 mmol, 244 mg) wasadded and the mixture stirred another hour. The mixture was concentratedunder vacuum (10°-25°, initial volume 2000 mL; final volume 400 mL) andmethylene chloride (400 mL) was added and the organic phase was washedwith aqueous sulfuric acid (1.0N, two 100 mL portions, pH 1-3) andsodium bicarbonate (1.0N, 50 mL, pH 9). The organic extracts were driedand clarified by filtration over approximately 20 g of 4Å molecularsieves. The mixture was concentrated under vacuum to a total weight of129.6 g.

Step C--Reduction-Cleavage

To about 103 g of the above residue were added 37 mL of triethylsilaneand 46 mL of trifluoroacetic acid at 25°. After 1.5 hours reduction wasapproximately 50% complete. After an additional 12 hours the reductionwas complete by TLC. The mixture was then refluxed for 2.5 hours. Themixture was allowed to cool and was concentrated in vacuo toapproximately 25 g. The residue above was dissolved in 400 mL ofmethylene chloride, washed with aqueous sodium hydroxide (enough for pH11), and concentrated under vacuum. This concentrate was then treatedwith diethyl ether (approximately 5 volumes at 22° then 0° for severalhours). The mixture was filtered and rinsed with several small portionsof ether affording the desired product after drying as a crystalline,white solid (yield=approximately 60% based on purity of bromotetralone).Analysis by reverse phase high performance liquid chromatography on aWaters NOVA-PAK instrument, C-18 3.9×150 mm column, eluting with 2ml/min. of 25% aqueous acetonitrile containing 1% ammonium acetate,operating the detector at 220 mm.

Potency: 91.2%

Related substances: 6.8%

Anal Calcd for C₁₄ H₁₆ NOBr: C, 57.16; H, 5.48; N, 4.76; Br, 27.16Found: C, 55.08; H, 5.43; N, 4:30; Br, 27.78 ¹³ C NMR (CDCl₃): 21.60,24.62, 28.24, 29.48, 33.15, 36.90, 57.28, 121.03,127.42, 130.09, 132.86,137.51, 143.26, 173.62 1H NMR (CDCl₃): 1.18 (s, 3H)

α589 nm-90°

α365 nm-302°

ee%>98%, determined by chromatography on a Chiracel-OD instrument and 1mL/min, 40°, eluting with 10% isopropanol in hexane and operating thedetector at 220 nm.

PREPARATION 3 Acrylic Anhydride

Two hundred fifty ml of tetrahydrofuran was added to a 1 liter jacketedflask with stir bar and nitrogen purge, and 250 mg of butylatedhydroxytoluene, 250 mg of hydroquinone and 25.3 g of triethylamine wereadded. The solution was cooled to 0°, and to it was added 18.0 g ofacrylic acid over a 2 minute period. The solution was cooled again to0°, and 22.6 g of acryloyl chloride was added over a 10 minute period.It is important to maintain the addition rate constant during theacryloyl chloride addition. Maintaining the jacket temperature at 0° andcontinuing the nitrogen purge, the solution was stirred for 1 hour, andthen it was filtered in a vacuum filter and the cake was washed with 50ml of additional tetrahydrofuran.

PREPARATION 4(R)-6-chloro-2-(1-phenylethylamino)-3,4-dihydronaphthalene, lithium salt

6-Chloro-2-tetralone (4.51 g, 25 mmol) was reacted with 3.32 g of(R)-(+)-phenethylamine and 20 mg of p-toluene-sulfonic acid. Thereaction was carried out as shown in Preparation 1 above in 100 mL oftoluene, and when the reaction was complete the mixture was concentratedunder vacuum and the residue was dissolved in 70 mL of tetrahydrofuran.The solution was cooled to -50 to -60°, and was added quickly to asolution of 1.15 equivalents of lithium diisopropylamide in 122 mL oftetrahydrofuran at -70° to -65°. The solution was allowed to warm to-20° for 20 minutes, and was then quickly recooled to -75°.

PREPARATION 5(4aR)-(10bR)-8-chloro-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

To the cold solution from Preparation 4, was added 1.15 equivalents ofmethyl iodide, and the mixture was allowed to warm to -5° over a 15minute period with continued good stirring. Then 1.3 equiv. ofmethanesulfonic acid was added to the mixture over a 5 minute period.

That mixture was vigorously stirred for 10 minutes at -5°, and was thencooled again to -75°. To it was added in one portion, 2.4 equiv. ofacrylic anhydride, with continued stirring, and the mixture was allowedto warm from -75° to 15° over a period of 13 hours.

The resulting reaction mixture was poured into a well stirred solutionof aqueous sodium bicarbonate (2 g/200 mL at 20°) and 100 mg ofdimethylaminopyridine. After two hours of stirring at ambienttemperature, most of the volatiles were removed under vacuum, and 130 mLof methylene chloride was added. The mixture was washed with 50 mL of 1Nhydrochloric acid, and then with aqueous sodium bicarbonate, and theorganic phase was dried and concentrated to a white foam (10.37 g).

The foam was placed in a flask in a ice bath and was treated with 40 mLtriethylsilane and 60 mL of trifluoroacetic acid for 15 hours at 0° andwas then held for four days at 25°. The volatiles were removed undervacuum, and the colorless oil was decanted from the solid product. Theresidue was dissolved in 200 mL of methylene chloride and washed withsaturated aqueous sodium bicarbonate. The extracts were dried with 4Amolecular sieves and evaporated. The residue was washed with 76 mL ofdiethyl ether to obtain 3.87 g of the desired product as a white solidadmixed with a small amount of isomeric material.

MS=249, 251 (M+, M+2)

IR (CHCl₃)=3396, 1662 cm⁻¹.

Anal Calcd for C₁₄ H₁₆ NOCl: C, 67.33; H, 6.46; N, 5.61; Cl, 14.20Found: C, 66.57; H, 6.43; N, 5.40; Cl, 13.91 ¹ H NMR (CDCl₃ 500 MHz):1.16(s, 3H), 3.54(d×d, 1H), UV (MeOH): γ205 (21000), 271 (600), 280(600)

The following group of examples illustrates the preparation of compoundswhere X is a sulfur atom by reactions with disulfides.

EXAMPLE 5(+)-(4aR)-(10bR)-8-(4-chlorophenylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

To a 3-necked 125 ml flask was added 50 ml of THF and 500 mg of(4aR)-(10bR)-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneat ambient temperature. The solution was cooled to -75°, and to it wasadded dropwise 1.7 ml of methyllithium in diethyl ether. The mixture wasstirred for 15 minutes, and then 2.4 ml of t-butyllithium (1.7M inpentane) was added and the temperature rose to -70°. The mixture wasstirred for 5 minutes and then 1.95 g of bis(4-chlorophenyl) disulfidedissolved in 10 ml of THF was added in portions. The reaction mixturewas stirred for 20 minutes at -75° and then was allowed to warm toambient temperature. It was acidified with 1N hydrochloric acid, and wasdiluted with 300 ml of ethyl acetate. The organic solution was washedsuccessively with 1N hydrochloric acid, 10% sodium carbonate solution,water and brine, and was then dried and concentrated under vacuum toobtain 2 g of a yellow oil. The oil was purified by chromatography oversilica gel, eluting with a solvent beginning with 2% methanol indichloromethane and going to 3% methanol/dichloromethane. Theproduct-containing fractions were evaporated to obtain 540 mg of foam,which was crystallized from ethyl acetate to obtain 453 mg of purifiedproduct. mp 169°-172° FDMS: m/e=357. α[D]₅₈₉ =+83.91, α[D]₃₆₅ =+293.47(methanol).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              67.12     67.33                                                H              5.63      5.82                                                 N              3.91      3.78                                                 ______________________________________                                    

EXAMPLE 6(+)-(4aR)-(10bR)-8-(4-methylphenylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 549 mg portion of the same intermediate used in Example 5 was reactedwith 1.84 g of bis(4-methylphenyl)-disulfide under conditions asdescribed in Example 5 to obtain 481 mg of the desired product. mp209°-212° FDMS: m/e=337. α[D]₅₈₉ =+85.00, α[D]₃₆₅ =+309.00 (chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              74.74     75.00                                                H              6.87      6.94                                                 N              4.15      4.10                                                 ______________________________________                                    

EXAMPLE 7

(+)-(4aR)-(10bR)-8-(2-chorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 910 mg portion of the same starting material used in Example 5 wasreacted with 3.6 g of bis(2-chorophenyl)disulfide as described inExample 5 to obtain 790 mg of the desired product. mp 189°-191° FDMS:m/e=357. α[D]₅₈₉ =+80.66, α[D]₃₆₅ =+281.3 (chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              67.12     67.30                                                H              5.63      5.52                                                 N              3.91      3.99                                                 ______________________________________                                    

EXAMPLE 8(+)-(4aR)-(10bR)-8-(3-chlorophenylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 930 mg portion of the same starting material as in Example 5 wasreacted with 3.6 g of bis (3-chlorophenyl)disulfide as described inExample 5 to obtain 810 mg of the desired product. mp 186°-187°. FDMS:m/e=357. α[D]₅₈₉ =+80.5, α[D]₃₆₅ =+292.6 (chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              67.12     67.41                                                H              5.63      5.82                                                 N              3.91      3.88                                                 ______________________________________                                    

EXAMPLE 9(+)-(4aR)-(10bR)-8-(2-methylphenylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 620 mg portion of the same starting material used in Example 5 wasreacted with 2.1 g of bis(2-methylphenyl)disulfide to obtain 490 mg ofthe desired product, using conditions as described in Example 5 above.mp 192°, 196°-199° FDMS: m/e=337. α[D]₅₈₉ =+87.8, α[D]₃₆₅ =+310.3(chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              74.74     74.46                                                H              6.87      6.90                                                 N              4.15      3.90                                                 ______________________________________                                    

EXAMPLE 10(+)-(4aR)-(10bR)-8-(3-methylphenylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 620 mg portion of the same starting material used in Example 5 wasreacted with 2.1 g of bis(3-methylphenyl)disulfide under the conditionsof Example 5 to obtain 480 mg of the desired product. mp 189°-191° FDMS:m/e=337. α[D]₅₈₉ =+87.8, α[D]₃₆₅ =+316.5 (chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              74.74     75.02                                                H              6.87      6.90                                                 N              4.15      4.34                                                 ______________________________________                                    

EXAMPLE 11(+)-(4aR)-(10bR)-8-(1-naphthylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 630 mg portion of the same starting material used in Example 5 wasreacted with 2.73 g of bis(1-naphthyl)disulfide under the conditions ofExample 5 to obtain 555 mg of the desired product. mp 199°-201° FDMS:m/e=373. α[D]₅₈₉ =+76.7, α[D]₃₆₅ =+238.6 (chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              77.18     76.96                                                H              6.21      6.12                                                 N              3.75      3.64                                                 ______________________________________                                    

EXAMPLE 12(+)-(4aR)-(10bR)-8-(2-methoxyphenylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 700 mg portion of the same starting material used in Example 5 wasreacted with 2.65 g of bis (2-methoxyphenyl)-disulfide under theconditions of Example 5 to obtain 580 mg of the desired product. mp176°-179° FDMS: m/e=353. α[D]₅₈₉ =+80.4, α[D]₃₆₅ =+287.9 (chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              71.36     71.64                                                H              6.56      6.46                                                 N              3.96      3.72                                                 ______________________________________                                    

EXAMPLE 13 (+)-(4aR)-(10bR)-8-(4-methoxyphenylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 700 mg portion of the same starting material used in Example 5 wasreacted with 2.65 g of bis(4-methoxyphenyl)-disulfide under theconditions of Example 5 to obtain 630 mg of the desired product. mp194°-196° FDMS: m/e=353. α[D]₅₈₉ =+86.2, α[D]₃₆₅ =+309.4 (chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              71.36     71.21                                                H              6.56      6.51                                                 N              3.96      3.71                                                 ______________________________________                                    

EXAMPLE 14 (+)-(4aR)-(10bR)-8-(4-fluorophenylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 700 mg portion of the same starting material used in Example 5 wasreacted with 2.4 g of bis(4-fluorophenyl)disulfide under the conditionsof Example 5 to obtain 600 mg of the desired product. mp 179°-181° FDMS:m/e=341. α[D]₅₈₉ =+88.9, α[D]₃₆₅ =+313.2 (chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              70.35     70.07                                                H              5.90      5.85                                                 N              4.10      3.83                                                 ______________________________________                                    

EXAMPLE 15(4aR)-(10bR)-8-(3-methoxyphenylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 700 mg portion of the same starting material used in Example 5 wasreacted with 2.65 g of bis(3-methoxyphenyl)disulfide under theconditions of Example 5 to obtain 650 mg of the desired product. mp154.5°-155.5° FDMS: m/e=353.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              71.36     71.29                                                H              6.56      6.56                                                 N              3.96      3.91                                                 ______________________________________                                    

EXAMPLE 16(+)-(4aR)-(10bR)-8-(3-fluorophenylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 700 mg portion of the same starting material used in Example 5 wasreacted with 2.4 g of bis(3-fluorophenyl)-disulfide under the conditionsof Example 5 to obtain 600 mg of the desired product. mp 154°-156° FDMS:m/e=341. α[D]₅₈₉ =+84.8, α[D]₃₆₅ =+300.6 (chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              70.35     70.38                                                H              5.90      5.96                                                 N              4.10      4.09                                                 ______________________________________                                    

EXAMPLE 17(+)-(4aR)-(10bR)-8-(2-fluorophenylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 700 mg portion of the same starting material used in Example 5 wasreacted with 2.4 g of bis(2-fluorophenyl)-disulfide under the conditionsof Example 5 to obtain 640 mg of the desired product. mp 196°-198° FDMS:m/e=341. α[D]₅₈₉ =+84.2, α[D]₃₆₅ =+300.8 (chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              70.35     70.24                                                H              5.90      5.95                                                 N              4.10      3.97                                                 ______________________________________                                    

EXAMPLE 18(4aR)-(10bR)-8-(3-quinolinylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 750 mg portion of the same starting material used in Example 5 wasreacted with 3.27 q of bis(3-quinolinyl)-disulfide under the conditionsof Example 5 to obtain 340 mg of the desired product. mp 168°-170° FDMS:m/e=374.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              73.76     73.56                                                H              5.92      5.96                                                 N              7.48      7.36                                                 ______________________________________                                    

EXAMPLE 19(4aR)-(10bR)-8-(2-quinolinylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 750 mg portion of the same starting material used in Example 5 wasreacted with 3.27 g of bis(2-quinolinyl)-disulfide under the conditionsof Example 5 to obtain 560 mg of the desired product. mp 2200°-222°FDMS: m/e=374.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              73.76     73.56                                                H              5.92      5.92                                                 N              7.48      7.40                                                 ______________________________________                                    

EXAMPLE 20(+)-(4aR)-(10bR)-8-(8-quinolinylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 750 mg portion of the same starting material used in Example 5 wasreacted with 3.27 g of bis(8-quinolinyl)-disulfide to obtain 375 mg ofthe desired product. mp>260° FDMS: m/e=374. α[D]₅₈₉ =+71.6, α[D]₃₆₅=absorbance (chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              73.76     73.61                                                H              5.92      5.99                                                 N              7.48      7.46                                                 ______________________________________                                    

EXAMPLE 21(4aR)-(10bR)-8-(2-pyridinylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 750 mg portion of the same starting material used in Example 5 wasreacted with 2.25 g of bis(2-pyridinyl)-disulfide as described inExample 5 to obtain 530 mg of the desired product. mp 223°-225° FDMS:m/e=324.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              70.34     70.09                                                H              6.21      6.24                                                 N              8.63      8.57                                                 ______________________________________                                    

EXAMPLE 22 (4aR)-(10bR)-8-phenylthio-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 500 mg portion of the same starting material used in Example 5 wasreacted with 414 g of diphenyldisulfide as described in Example 5 toobtain 351 mg of the desired product. mp 183°-185° FDMS: m/e=323.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              74.27     73.99                                                H              6.54      6.68                                                 N              4.33      4.53                                                 ______________________________________                                    

EXAMPLE 23 (4aR)-(10bR)-8-benzylthio-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 501 mg portion of the same starting material used in Example 5 wasreacted with 1.0 g of dibenzyldisulfide substantially as described inExample 5 to obtain 329 mg of the desired product. mp 172°-174° FDMS:m/e=337. α[D]₅₈₉ =80.84 (c=0.57 in chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              74.74     74.49                                                H              6.87      6.85                                                 N              4.15      4.18                                                 ______________________________________                                    

The following group of examples demonstrates syntheses in which abromine-substituted benzoquinolinone nucleus compound is reacted with acompound having a boronic acid leaving group and providing the R⁵ group,where X is a bond.

EXAMPLE 24(+)-(4aR)-(10bR)-4-methyl-8-(4-chloro-3-trifluoromethyl-phenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 4-chloro-3-trifluoromethylphenylboronic acid (175 mg, 0.78mmol), 0.65 mL of 2M aq. sodium carbonate solution and 2 mL of THF,fitted with a reflux condenser, and the stirred mixture was heated at80°, under nitrogen, for 16 h. The mixture was cooled, diluted withchloroform (50 mL) and washed with brine (2×25 mL). The combined organicextracts were dried over sodium sulfate, concentrated, and purified bysilica gel chromatography (ethyl acetate eluent), to give 188 mg (71%)of the title compound as a white solid. mp 134°-137°. FDMS: m/e=407.α[D]₅₈₉ =+59.74 (c=1.02, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              64.79     64.78                                                H              5.19      5.23                                                 N              3.43      3.65                                                 ______________________________________                                    

EXAMPLE 25

(+)-(4aR)-(10bR)-4-methyl-8-(3-chloro-4-hydroxyphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 3-chloro-4-hydroxyphenylboronic acid (134 mg, 0.78mmol),0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fittedwith a reflux condenser, and the stirred mixture was heated at 80°,under nitrogen, for 24 h. The mixture was cooled, diluted withchloroform (50 mL) and washed with brine (2×25 mL). The combined organicextracts were dried over sodium sulfate, concentrated, and purified bysilica gel chromatography (ethyl acetate eluent), to give 139 mg (61%)of the title compound as a white solid. mp 245° FDMS: m/e=355. α[D]₅₈₉=+17.62 (c=1.02, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              70.88     70.74                                                H              6.23      6.27                                                 N              3.94      4.10                                                 ______________________________________                                    

EXAMPLE 26(+)-(4aR)-(10bR)-4-methyl-8-(2,3-difluorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 2,3-difluorophenylboronic acid (123 mg, 0.78 mmol), 0.65 mLof 2M sodium carbonate solution and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 16 h. Additional palladium reagent was added, and the mixture washeated for an additional 16 h. The mixture was cooled, diluted withchloroform (75 mL) and washed with brine (2×25 mL). The combined organicextracts were dried over sodium sulfate, concentrated, and purified bysilica gel chromatography (ethyl acetate eluent) to give 111 mg (50%) ofthe title compound as a white solid. mp 147°-148°. FDMS: m/e=341 α[D]₅₈₉=+70.44 (c=1.08, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              73.88     73.79                                                H              6.20      6.27                                                 N              4.10      4.16                                                 ______________________________________                                    

EXAMPLE 27(+)-(4aR)-(10bR)-4-methyl-8-(3,4-difluorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 3,4-difluorophenylboronic acid (123 mg, 0.78 mmol),0.65 mLof 2M sodium carbonate solution and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24 h. Additional palladium reagent and boronic acid was added, andthe mixture was heated for an additional 24 h. The mixture was cooled,diluted with chloroform (75 mL) and washed with brine (2×25 mL). Thecombined organic extracts were dried over sodium sulfate, concentrated,and purified by silica gel chromatography (ethyl acetate eluent) to give130 mg (58%) of the title compound as a white solid. mp 143°-148°. FDMS:m/e=341 α[D]₅₈₉ =+65.12 (c=0.97, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              73.88     73.90                                                H              6.20      6.21                                                 N              4.10      3.86                                                 ______________________________________                                    

EXAMPLE 28(+)-(4aR)-(10bR)-4-methyl-8-(3-fluoro-4-hydroxyphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 3-fluoro-4-hydroxyphenylboronic acid (122 mg, 0.78 mmol),0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with areflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 16 h. The mixture was cooled, diluted with chloroform (50mL) and washed with brine (2×50 mL). The combined organic extracts weredried over sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent), to give 111 mg (50%) of the titlecompound as a white solid. mp>240° C. FDMS: m/e=339. α[D]₅₈₉ =+11.21(c=1.07, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              74.31     74.12                                                H              6.53      6.53                                                 N              4.13      3.88                                                 ______________________________________                                    

EXAMPLE 29(+)-(4aR)-(10bR)-4-methyl-8-(3,4-ethylenedioxyphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 3,4-ethylenedioxyphenylboronic acid (140 mg, 0.78 mmol),0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with areflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 24 h. The mixture was cooled, diluted with chloroform (50mL) and washed with brine (2×25 mL). The combined organic extracts weredried over sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent), to give 189 mg (80%) of the titlecompound as an amorphous solid. mp 183°-189°. FDMS: m/e=363. α[D]₅₈₉=+80.77 (c=1.04, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              76.01     75.75                                                H              6.93      6.89                                                 N              3.85      3.62                                                 ______________________________________                                    

EXAMPLE 30 (+)-(4aR)-(10bR)-4-methyl-8-(3,5-di[t-butyl]-4-hydroxy-phenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) {23 mg,0.02 mmol), 3,5-di(t-butyl)-4-hydroxyphenylboronic acid (195 mg, 0.78mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fittedwith a reflux condenser, and the stirred mixture was heated at 80°,under nitrogen, for 16 h. The mixture was cooled, diluted withchloroform (50 mL) and washed with brine (2×25 mL). The combined organicextracts were dried over sodium sulfate, concentrated, and purified bysilica gel chromatography (ethyl acetate eluent), to give 170 mg (58%)of the title compound as a white solid. mp>265°. FDMS: m/e=433 α[D]₅₈₉=+46.45 (c=1.00, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              80.33     78.52                                                H              9.06      9.01                                                 N              3.23      2.69                                                 ______________________________________                                    

EXAMPLE 31(+)-(4aR)-(10bR)-4-methyl-8-(2-trifluoromethyl-4-fluoro-phenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 2-trifluoromethyl-4-fluorophenylboronic acid (162 mg, 0.78mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fittedwith a reflux condenser, and the stirred mixture was heated at 80°,under nitrogen, for 24 h. The mixture was cooled, diluted withchloroform (75 mL) and washed with brine (2×25 mL). The combined organicextracts were dried over sodium sulfate, concentrated, and purified bysilica gel chromatography (ethyl acetate eluent), to give 96 mg (38%) ofthe title compound as an amorphous foam. mp 70° FDMS: m/e=391. α[D]₅₈₉=+55.81 (c=0.60, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              67.51     66.97                                                H              5.41      5.31                                                 N              3.58      3.07                                                 ______________________________________                                    

EXAMPLE 32(+)-(4aR)-(10bR)-4-methyl-8-(1-[4-t-butylcarbonyl-amino]-naphthyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo [f]-quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 4-(t-butylcarbonylamino)-1-naphthylboronic acid (211 mg,0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF,fitted with a reflux condenser, and the stirred mixture was heated at80°, under nitrogen, for 24 h. Additional palladium reagent and boronicacid was added, and the mixture was heated for an additional 24 h. Themixture was cooled, diluted with dichloromethane (75 mL) and washed withbrine (2×25 mL). The combined organic extracts were dried over sodiumsulfate, concentrated, and purified by silica gel chromatography (ethylacetate eluent), to give 239 mg (81%) of the title compound as anamorphous solid. mp>260°. FDMS: m/e=454. α[D]₅₈₉ =+46.85 (c=0.51,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              79.26     80.39                                                H              7.54      7.87                                                 N              6.16      5.82                                                 ______________________________________                                    

EXAMPLE 33(+)-(4aR)-(10bR)-4-methyl-8-(2-chloro-5-trifluoro-methylphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 2-chloro-5-trifluoromethylphenylboronic acid (175 mg, 0.78mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fittedwith a reflux condenser, and the stirred mixture was heated at 80°,under nitrogen, for 24 h. The mixture was cooled, diluted withchloroform (50 mL) and washed with brine (2×25 mL). The combined organicextracts were dried over sodium sulfate, concentrated, and purified bysilica gel chromatography (ethyl acetate eluent), to give 170 mg (64%)of the title compound as an oil. FDMS: m/e=407. α[D]₅₈₉ =+49.42 (c=0.58,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              64.79     65.65                                                H              5.19      5.39                                                 N              3.43      3.75                                                 ______________________________________                                    

EXAMPLE 34 (+)-(4aR)-(10bR)-4-methyl-8-(3-t-butylcarboxamido-phenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 3-(t-butylcarboxamido)phenylboronic acid (172 mg, 0.78mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fittedwith a reflux condenser, and the stirred mixture was heated at 80°,under nitrogen, for 24 h. The mixture was cooled, diluted withchloroform (75mL) and washed with brine (2×25 mL). The combined organicextracts were dried over sodium sulfate, concentrated, and purified bysilica gel chromatography (ethyl acetate eluent), to give 213 mg (81%)of the title compound as a waxy solid. FDMS: m/e=404. α[D]₅₈₉ =+54.34(c=0.45, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              77.19     77.45                                                H              7.97      7.93                                                 N              6.92      6.64                                                 ______________________________________                                    

EXAMPLE 35(+)-(4aR)-(10bR)-4-methyl-8-(2-[1-diethylcarboxamido]-naphthyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 1-(diethylcarboxamido)-2-naphthylboronic acid (211 mg, 0.78mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fittedwith a reflux condenser, and the stirred mixture was heated at 80°,under nitrogen, for 24 h. The mixture was cooled, diluted withchloroform (75 mL) and washed with brine (2×25 mL). The combined organicextracts were dried over sodium sulfate, concentrated, and purified bysilica gel chromatography (ethyl acetate eluent), to give 240 mg (81%)of the title compound as a white solid. mp 208°-211°. FDMS: m/e=454.α[D]₅₈₉ =+49.37 (c=0.51, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              79.26     77.29                                                H              7.54      7.57                                                 N              6.16      6.11                                                 ______________________________________                                    

EXAMPLE 36(+)-(4aR)-(10bR)-4-methyl-8-(4-hydroxy-3-methoxy-phenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 4-hydroxy-3-methoxyphenylboronic acid (131 mg, 0.78 mmol),0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with areflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75mL) and washed with brine (2×25 mL). The combined organic extracts weredried over sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent), to give 91 mg (40%) of the titlecompound as a white solid. mp 247°-250°. FDMS: m/e=351. α[D]₅₈₉ =+79.51(c=0.75, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              75.19     75.13                                                H              7.17      7.24                                                 N              3.99      3.97                                                 ______________________________________                                    

EXAMPLE 37(+)-(4aR)-(10bR)-4-methyl-8-(4-t-butylcarbonyl-aminophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (50 mg,0.04 mmol), 4-t-butylcarbonylaminophenylboronic acid (172 mg, 0.78mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fittedwith a reflux condenser, and the stirred mixture was heated at 80°,under nitrogen, for 24 h. The mixture was cooled, diluted withchloroform (50 mL) and washed with brine (2×25 mL). The combined organicextracts were dried over sodium sulfate, concentrated, and purified bysilica gel chromatography (ethyl acetate eluent), to give 104 mg (40%)of the title compound as a brown solid. mp>265° C. FDMS: m/e=404.α[D]₅₈₉ =+49.42 (c=0.56, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              77.19     76.92                                                H              7.97      8.07                                                 N              6.92      6.73                                                 ______________________________________                                    

EXAMPLE 38 (+)-(4aR)-(10bR)-4-methyl-8-(2-fluorophenyl)-10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 2-fluorophenylboronic acid (109 mg, 0.78 mmol), 0.65 mL of2M sodium carbonate solution and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 16 h. The mixture was cooled, diluted with chloroform (75 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent) to give 172 mg (82%) of the titlecompound as a foam. mp 142-150°. FDMS: m/e=323. α[D]₅₈₉ =+77.89 (c=0.69,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              77.99     78.09                                                H              6.86      6.95                                                 N              4.33      4.30                                                 ______________________________________                                    

EXAMPLE 39(+)-(4aR)-(10bR)-4-methyl-8-(2-methoxyphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 2-methoxyphenylboronic acid (119 mg, 0.78 mmol), 0.65 mL of2M sodium carbonate solution and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24h. The mixture was cooled, diluted with chloroform (50 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (EtOAc eluent), to give 160 mg (73%) of the titlecompound as a white solid. mp 152°-156°. FDMS: m/e=335. α[D]₅₈₉ =+77.45(c=0.64, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              78.77     78.53                                                H              7.51      7.25                                                 N              4.18      4.35                                                 ______________________________________                                    

EXAMPLE 40(+)-(4aR)-(10bR)-4-methyl-8-(2-methylphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 2-methylphenylboronic acid (106 mg, 0.78 mmol), 0.65 mL of2M sodium carbonate solution and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24 h. The mixture was cooled, diluted with chloroform (75 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent), to give 146 mg (70%) of the titlecompound as an amorphous solid. mp 82°-87°. FDMS: m/e=319. α[D]₅₈₉=+63.96 (c=0.35, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              82.72     82.63                                                H              7.89      7.95                                                 N              4.38      4.10                                                 ______________________________________                                    

EXAMPLE 41(+)-(4aR)-(10bR)-4-methyl-8-(2-chlorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 2-chlorophenylboronic acid (122 mg, 0.78 mmol) ,0.65 mL of2M sodium carbonate solution and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24 h. The mixture was cooled, diluted with chloroform (75 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent), to give 186 mg (84 %) of thetitle compound as an amorphous foam. mp 111°-120°. FDMS: m/e=339.α[D]₅₈₉ =56.86 (c=0.64, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              74.22     74.50                                                H              6.52      6.46                                                 N              4.12      3.82                                                 ______________________________________                                    

EXAMPLE 42(+)-(4aR)-(10bR)-4-methyl-8-(3,4-dimethoxyphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 3,4-dimethoxyphenylboronic acid (142 mg, 0.78 mmol), 0.65 mLof 2M sodium carbonate solution and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24 h. The mixture was cooled, diluted with chloroform (75 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent), to give 171 mg (72%) of the titlecompound as an amorphous foam. mp 108°-112°. FDMS: m/e=365. α[D]₅₈₉=+73.75 (c=0.56, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              75.59     75.88                                                H              7.45      7.57                                                 N              3.83      3.85                                                 ______________________________________                                    

EXAMPLE 43(+)-(4aR)-(10bR)-4-methyl-8-(2-trifluoromethylphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 2-trifluoromethylphenylboronic acid (148 mg, 0.78 mmol),0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with areflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 24 h. The mixture was cooled, diluted with CHCl₃ (75 mL)and washed with brine (2×25 mL). The combined organic extracts weredried over sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent), to give 201 mg (83%) of the titlecompound as an oil. FDMS: m/e=373. α[D]₅₈₉ =+60.00 (c=0.36, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              70.76     70.55                                                H              5.94      7.97                                                 N              3.75      3.49                                                 ______________________________________                                    

EXAMPLE 44 (+)-(4aR)-(10bR)-4-methyl-8-(3-fluorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 3-fluorophenylboronic acid (109 mg, 0.78 mmol) ,0.65 mL of2M sodium carbonate solution and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 18 h. The mixture was cooled, diluted with chloroform (75 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent), to give 177 mg (84%) of the titlecompound as an amorphous foam. mp 116°-120°. FDMS: m/e=323. α[D]₅₈₉=+81.84 (c=0.47, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              77.99     77.69                                                H              6.86      6.85                                                 N              4.33      4.11                                                 ______________________________________                                    

EXAMPLE 45(+)-(4aR)-(10bR)-8-(3-quinolinyl)-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (168 mg, 0.65 mmol) (prepared in Prep. 9 below),tetrakis(triphenylphosphine)-palladium(0) (23 mg, 0.02 mmol),3-bromoquinoline (135 mg, 0.65 mmol), 0.65 mL of 2M sodium carbonate and2 mL of THF, fitted with a reflux condenser, and the stirred mixture washeated at 80°, under nitrogen, for 24 h. The mixture was cooled, dilutedwith chloroform (75 mL) and washed with brine (2×25 mL). The combinedorganic extracts were dried over sodium sulfate, concentrated, andpurified by silica gel chromatography (5% methanol/ethyl acetate eluent)to give 141 mg (63%) of the title compound as a white solid. mp265°-266° FDMS: m/e=342. α[D]₅₈₉ =+88.70 (c=0.84, chloroform).

EXAMPLE 46(+)-(4aR)-(10bR)-4-methyl-8-(4-fluoro-3-trifluoro-methyl-phenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 4-fluoro-3-trifluoromethylphenylboronic acid (162 mg, 0.78mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fittedwith a reflux condenser, and the stirred mixture was heated at 80°,under nitrogen, for 18 h. The mixture was cooled, diluted withchloroform (75 mL) and washed with brine (2×25 mL). The combined organicextracts were dried over sodium sulfate, concentrated, and purified bysilica gel chromatography (ethyl acetate eluent) to give 110 mg (43%) ofthe title compound as an amorphous foam. FDMS: m/e=323. α[D]₅₈₉ =+51.47(c=0.52, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              67.51     67.80                                                H              5.41      5.46                                                 N              3.58      3.32                                                 ______________________________________                                    

EXAMPLE 47(+)-(4aR)-(10bR)-4-methyl-8-(4-methoxyphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 4-methoxyphenylboronic acid (119 mg, 0.78 mmol), 0.65 mL of2M sodium carbonate solution and 1.5 mL of toluene, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 16 h. The mixture was cooled, diluted with dichloromethane (75 mL)and washed with brine (2×25 mL). The combined organic extracts weredried over sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent), followed by recrystallizationfrom ethyl acetate to give 173 mg (79%) of the title compound as a whitesolid. mp 150°. FDMS: m/e=335. α[D]₅₈₉ =+73.82 (c=1.01, methanol).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              78.77     78.49                                                H              7.51      7.44                                                 N              4.18      4.43                                                 ______________________________________                                    

EXAMPLE 48(+)-(4aR)-(10bR)-4-methyl-8-(3-methoxyphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 3-methoxyphenylboronic acid (119 mg, 0.78 mmol), 0.65 mL of2M sodium carbonate solution and 1.5 mL of toluene fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24 h . The mixture was cooled, diluted with dichloromethane (75 mL)and washed with brine (2×25 mL). The combined organic extracts weredried over sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent) to give 144 mg (66%) of the titlecompound as a white solid. mp 140°. FDMS: m/e=335. α[D]₅₈₉ =+77.45(c=1.02, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              78.77     78.53                                                H              7.51      7.50                                                 N              4.18      3.92                                                 ______________________________________                                    

EXAMPLE 49(+)-(4aR)-{10bR)-4-methyl-8-phenyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23mg,0.02 mmol), phenylboronic acid (95 mg, 0.78 mmol) ,0.65 mL of 2M sodiumcarbonate solution and 2 mL of toluene, fitted with a reflux condenser,and the stirred mixture was heated at 80°, under nitrogen, for 24 h. Themixture was cooled, diluted with dichloromethane (75 mL) and washed withbrine (2×25 mL). The combined organic extracts were dried over sodiumsulfate, concentrated, and purified by silica gel chromatography (ethylacetate eluent), followed by recrystallization from ethyl acetate, togive 139 mg (70%) of the title compound as a white solid. mp 155°. FDMS:m/e=305.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              82.59     82.79                                                H              7.59      7.59                                                 N              4.59      4.39                                                 ______________________________________                                    

EXAMPLE 50(+)-(4aR)-(10bR)-4-methyl-8-(4-chlorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 4-chlorophenylboronic acid (122 mg, 0.78 mmol), 0.65 mL of2M sodium carbonate solution and 2 mL of toluene, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 16h. The mixture was cooled, diluted with dichloromethane (75 mL)and washed with brine (2×25 mL). The combined organic extracts weredried over sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent), followed by recrystallizationfrom ethyl acetate, to give 166 mg (75%) of the title compound as awhite solid. mp 192°. FDMS: m/e=339. α[D]₅₈₉ =+76.14 (c=1.00,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              74.22     74.17                                                H              6.52      6.68                                                 N              4.12      3.97                                                 ______________________________________                                    

EXAMPLE 51(+)-(4aR)-(10bR)-4-methyl-8-(4-methylphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 4-methylphenylboronic acid (106 mg, 0.78 mmol), 0.65 mL of2M sodium carbonate solution and 2 mL of toluene, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 17 h. The mixture was cooled, diluted with dichloromethane (75 mL)and washed with brine (2×25 mL). The combined organic extracts weredried over sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent), followed by recrystallizationfrom ethyl acetate, to give 150 mg (72%) of the title compound as awhite solid. mp 178°. FDMS: m/e=319. α[D]₅₈₉ =+77.14 (c=1.00,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              82.72     82.66                                                H              7.89      7.95                                                 N              4.38      4.20                                                 ______________________________________                                    

EXAMPLE 52(+)-(4aR)-(10bR)-4-methyl-8-(3,5-dichlorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 3,5-dichlorophenylboronic acid (149 mg, 0.78 mmol), 0.65 mLof 2M sodium carbonate solution and 1.5 mL of toluene, fitted with areflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 24 h. The mixture was cooled, diluted with dichloromethane(75 mL) and washed with brine (2×25 mL). The combined organic extractswere dried over sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent), followed by recrystallizationfrom ethyl acetate to give 145 mg (60%) of the title compound as a whitesolid. mp 172° FDMS: m/e=374 α[D]₅₈₉ =+70.91 (c=0.55, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              67.39     67.43                                                H              5.65      5.67                                                 N              3.74      3.65                                                 ______________________________________                                    

EXAMPLE 53(+)-(4aR)-(10bR)-4-methyl-8-(1-naphthyl)-10b-methyl-2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 1-naphthylboronic acid (134 mg, 0.78 mmol), 0.65 mL of 1Msodium hydroxide solution and 2 mL of benzene, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24 h. The mixture was cooled, diluted with dichloromethane (75 mL)and washed with brine (2×25 mL). The combined organic extracts weredried over sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent), followed by recrystallizationfrom ethyl acetate to give 116 mg (50%) of the title compound as a whitesolid. mp 159°. FDMS: m/e=355. α[D]₅₈₉ =+60.00 (c=0.50, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              84.47     84.73                                                H              7.09      7.08                                                 N              3.94      3.89                                                 ______________________________________                                    

EXAMPLE 54(+)-(4aR)-(10bR)-4-methyl-8-(3-pyridyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (30 mg,0.03 mmol), tetrabutylammonium bromide (17 mg, 0.05 mmol),diethyl(3-pyridyl)borane (148 mg, 0.98 mmol), powdered potassiumhydroxide (85 mg, 1.4 mmol) and 3 mL of DME, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24 h. The mixture was cooled, diluted with water (15 mL), extractedwith 10% methanol in dichloromethane (2×50 mL) and washed with brine(2×25 mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (ethyl acetateeluent), to give 112 mg (56%) of the title compound as a white solid. mp135°. FDMS: m/e=306.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              78.40     78.37                                                H              7.24      7.37                                                 N              9.14      9.14                                                 ______________________________________                                    

EXAMPLE 55(+)-(4aR)-(10bR)-4-methyl-8-(3-biphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 3-biphenylboronic acid (154 mg, 0.78 mmol), 0.65 mL of 2Msodium carbonate solution and 2 mL of toluene, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24 h. The mixture was cooled, diluted with dichloromethane/ether(3:1, 75 mL) and washed with brine (2×25 mL). The combined organicextracts were dried over sodium sulfate, concentrated, and purified bysilica gel chromatography (ethyl acetate eluent), to give 176 mg (71%)of the title compound as a white solid. mp 131°. FDMS: m/e=381. α[D]₅₈₉=+71.15 (c=0.52, CHCl₃).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              85.00     84.77                                                H              7.13      7.31                                                 N              3.67      3.46                                                 ______________________________________                                    

EXAMPLE 56(+)-(4aR)-(10bR)-4-methyl-8-(4-phenoxyphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 4-phenoxyphenylboronic acid (167 mg, 0.78 mmol), 0.65 mL of2M sodium carbonate solution and 2 mL of toluene, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24h. The mixture was cooled, diluted with chloroform (75 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent), to give 206 mg (80%) of the titlecompound as a white solid. mp 148°-150°. FDMS: m/e=397. α[D]₅₈₉ =+64.51(c=0.62, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              81.58     81.47                                                H              6.85      8.83                                                 N              3.52      3.60                                                 ______________________________________                                    

EXAMPLE 57(+)-(4aR)-(10bR)-4-methyl-8-(3-formylphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 3-formylphenylboronic acid (117 mg, 0.78 mmol), 0.65 mL of2M sodium carbonate solution and 2 mL of toluene, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen for24 h. The mixture was cooled, diluted with dichloromethane (75 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent), to give 141 mg (65%) of the titlecompound as a white solid. mp 163°. FDMS: m/e=333.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              79.25     79.16                                                H              6.95      6.99                                                 N              4.20      3.92                                                 ______________________________________                                    

EXAMPLE 58(+)-(4aR)-(10bR)-4-methyl-8-(3-formyl-4-hydroxyphenyl)-(10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 3-formyl-4-hydroxyphenylboronic acid (129 mg, 0.78 mmol),0.65 mL of 2M sodium carbonate solution and 2 mL of toluene, fitted witha reflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 24 h. Additional palladium reagent and boronic acid wasadded, and the mixture was heated for an additional 24 h. The mixturewas cooled, diluted with dichloromethane (75 mL) and washed with brine(2×25 mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (ethyl acetateeluent), followed by recrystallization from ethyl acetate, to give 85 mg(37%) of the title compound as a white solid. mp 184°-187°. FDMS:m/e=349.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              75.62     75.86                                                H              6.63      6.72                                                 N              4.01      3.87                                                 ______________________________________                                    

EXAMPLE 59(+)-(4aR)-(10bR)-4-methyl-8-(4-dimethylaminophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 4-dimethylaminophenylboronic acid (129 mg, 0.78 mmol), 0.65mL of 2M sodium carbonate solution and 2 mL of toluene, fitted with areflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 17 h. The mixture was cooled, diluted with dichloromethane(75 mL) and washed with brine (2×25 mL). The combined organic extractswere dried over sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent), to give 119 mg (53%) of the titlecompound as an amorphous foam. mp 197°-202°. FDMS: m/e=348. α[D]₅₈₉=+76.84 (c=0.95, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              78.27     77.92                                                H              8.10      8.12                                                 N              8.04      7.84                                                 ______________________________________                                    

EXAMPLE 60(+)-(4aR)-(10bR)-4-methyl-8-(2-[6-hydroxy]naphthyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (50 mg,0.04 mmol), 6-hydroxy-2-naphthylboronic acid (147 mg, 0.78 mmol), 0.65mL of 2M sodium carbonate solution and 2 mL of toluene, fitted with areflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 24 h. Additional palladium reagent and boronic acid wasadded, and the mixture was heated for an additional 24 h. The mixturewas cooled, diluted with dichloromethane (75 mL) and washed with brine(2×25 mL). The aqueous layer was acidified with 5N hydrochloric acid,and extracted with dichloromethane. The combined organic extracts weredried over sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent) to give 47 mg (20%) of the titlecompound as a white solid. mp>260° (decomp.) FDMS: m/e=371.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              80.83     79.84                                                H              6.78      6.73                                                 N              3.77      3.25                                                 ______________________________________                                    

EXAMPLE 61(+)-(4aR)-(10bR)-4-methyl-8-(9-anthracenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 9-anthracenylboronic acid (159 mg, 0.78 mmol), 0.65 mL ofsodium carbonate and 2 mL of toluene, fitted with a reflux condenser,and the stirred mixture was heated at 80°, under nitrogen, for 48 h. Themixture was cooled, diluted with chloroform (75 mL) and washed withbrine (2×25 mL). The combined organic extracts were dried over sodiumsulfate, concentrated, and purified by silica gel chromatography (EtOAceluent) to give 112 mg (43%) of the title compound as an amorphoussolid. mp 95°-110°. FDMS: m/e=405. α[D]₅₈₉ =+45.73 (c=0.66, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              85.89     84.93                                                H              6.71      6.55                                                 N              3.45      3.01                                                 ______________________________________                                    

EXAMPLE 62(+)-(4aR)-(10bR)-4-methyl-8-(2-[6-benzyloxy]naphthyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 6-benzyloxy-2-naphthylboronic acid (200 mg, 0.72 mmol), 0.65mL of 2M sodium carbonate solution and 2 mL of toluene, fitted with areflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 24 h. Additional palladium reagent and Doronic acid wasadded, and the mixture was heated for an additional 24 h. The mixturewas cooled, diluted with dichloromethane (75 mL) and washed with brine(2×25 mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (ethyl acetateeluent), followed by recrystallization from ethyl acetate, to give 73 mg(24%) of the title compound as a white solid. mp 173°-176° FDMS:m/e=361. α[D]₅₈₉ =+66.07 (c=0.56, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              83.26     83.50                                                H              6.77      6.84                                                 N              3.03      3.03                                                 ______________________________________                                    

EXAMPLE 63(+)-(4aR)-(10bR)-4-methyl-8-(3-chlorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 3-chlorophenylboronic acid (122 mg, 0.78 mmol), 0.65 mL of2M sodium carbonate solution and 1.5 mL of toluene, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24 h. The mixture was cooled, diluted with dichloromethane (75 mL)and washed with brine (2×25 mL). The combined organic extracts weredried over sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent), to give 164 mg (74%) of the titlecompound as an amorphous foam. mp 158°-65°. FDMS: m/e=339. α[D]₅₈₉=+74.90 (c=1.00, methanol).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              74.22     73.95                                                H              6.52      6.51                                                 N              4.12      4.89                                                 ______________________________________                                    

EXAMPLE 64(+)-(4aR)-(10bR)-4-methyl-8-(1-[4-fluoro]naphthyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10-b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 4-fluoro-1-naphthylboronic acid (148 mg, 0.78 mmol),triethylamine (0.2 mL, 1.3 mmol), and 2 mL of DME, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24 h. The mixture was cooled, diluted with dichloromethane (75 mL)and washed with brine (2×25 mL). The combined organic extracts weredried over sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent), to give 188 mg (77%) of the titlecompound as an amorphous foam. mp 115°-125°. FDMS: m/e=373. α[D]₅₈₉=+60.78 (c=1.02, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              80.40     78.80                                                H              6.48      6.35                                                 N              3.75      3.41                                                 ______________________________________                                    

EXAMPLE 65(+)-(4aR)-(10bR)-4-methyl-8-(1-[4-methyl]naphthyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium (0) (23 mg,0.02 mmol), 4-methyl-1-naphthylboronic acid (145 mg, 0.78 mmol),triethylamine (0.2 mL, 1.3 mmol), and 2 mL of dimethyl ether, fittedwith a reflux condenser, and the stirred mixture was heated at 80°,under nitrogen, for 24 h. The mixture was cooled, diluted withdichloromethane (75 mL) and washed with brine (2×25 mL). The combinedorganic extracts were dried over sodium sulfate, concentrated, andpurified by silica gel chromatography (ethyl acetate eluent), followedby recrystallization from diethyl ether to give 36 mg (15%) of the titlecompound as a white solid. mp 175°-178°. FDMS: m/e=369. α[D]₅₈₉ =+63.81(c=1.05, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              84.51     84.73                                                H              7.36      7.44                                                 N              3.79      3.54                                                 ______________________________________                                    

EXAMPLE 66(+)-(4aR)-(10bR)-4-methyl-8-(5-acenaphthenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 5-acenaphtheneboronic acid (154 mg, 0.78 mmol), 0.20 mL oftriethylamine and 2 mL of DME, fitted with a reflux condenser, and thestirred mixture was heated at 80°, under nitrogen, for 24 h. The mixturewas cooled, diluted with chloroform (75 mL) and washed with brine (2×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (ethyl acetateeluent) to give 170 mg (69%) of the title compound as a white solid.mp>200° (decomp.) FDMS: m/e=381 α[D]₅₈₉ =+61.47(c=0.84, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              85.00     85.24                                                H              7.13      7.17                                                 N              3.67      3.51                                                 ______________________________________                                    

EXAMPLE 67(+)-(4aR)-(10bR)-4-methyl-8-(9-phenanthrenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 9-phenanthreneboronic acid (173 mg, 0.78 mmol),triethylamine (0.2 mL, 1.3 mmol), and 2 mL of dimethyl ether, fittedwith a reflux condenser, and the stirred mixture was heated at 80°,under nitrogen, for 24 h. The mixture was cooled, diluted withchloroform (75 mL) and washed with brine (2×25 mL). The combined organicextracts were dried over sodium sulfate, concentrated, and purified bysilica gel chromatography (ethyl acetate eluent), to give 80 mg (30%) ofthe title compound as a white solid. mp 218°-220°. FDMS: m/e=405.α[D]₅₈₉ =+63.01 (c=0.98, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              85.89     86.06                                                H              6.71      6.83                                                 N              3.45      3.39                                                 ______________________________________                                    

EXAMPLE 68

(+)-(4aR)-(10bR)-4-methyl-8-(4-[N-propyl, N-cyclopropyl-methylamino]-1-naphthyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 4-(N-propyl,N-cyclopropylmethylamino)-1-naphthyl-boronic acid (249 mg, 0.78 mmol),1.8 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with areflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75mL) and washed with brine (2×50 mL). The combined organic extracts weredried over sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent), to give 193 mg (64%) of the titlecompound as an oil. FDMS: m/e=466. α[D]₅₈₉ =+50.52 (c=0.95, chloroform).

EXAMPLE 69

(+)-(4aR)-(10bR)-4-methyl-8-(2,3-dimethylphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 2,3-dimethylphenylboronic acid (117 mg, 0.78 mmol), 0.65 mLof 2M sodium carbonate solution and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24 h. The mixture was cooled, diluted with chloroform (50 mL) andwashed with brine (2×50 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent), to give 55 mg (25%) of the titlecompound as an amorphous solid. mp 133°-140° FDMS: m/e=333. α[D]₅₈₉+61.90 (c=1.05, methanol).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              82.84     82.64                                                H              8.16      8.07                                                 N              4.20      4.15                                                 ______________________________________                                    

EXAMPLE 70

(+)-(4aR)-(10bR)-4-methyl-8-(3,4-methylenedioxyphenyl)-10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenz[f]quinolin-3-one

A 15 mL round bottom flask was charged with (+)-(4aR)-10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one 200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol),3,4-methylenedioxyphenyl boronic acid (131 mg, 0.78 mmol), 0.65 mL of 2Msodium carbonate solution and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24 h. The mixture was cooled, diluted with chloroform (50 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent), to give 130 mg (57%) of the titlecompound as an amorphous solid. mp 146°-152° FDMS: m/e=349. α[D]₅₈₉=+67.92 (c=1.06, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              75.62     75.46                                                H              6.63      6.77                                                 N              4.01      3.80                                                 ______________________________________                                    

EXAMPLE 71

(+)-(4aR)-(10bR)-4-methyl-8-(2-naphthyl)-10b-methyl1,2,3,4,4a,5,6,10b-octahydrobenzo[f ]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 2-naphthylboronic acid (168 mg, 0.98 mmol) ,0.65 mL of 2Msodium carbonate solution and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80° for 16 h. Themixture was cooled, diluted with chloroform (75 mL) and washed withbrine (2×25 mL). The combined organic extracts were dried over sodiumsulfate, concentrated, and purified by silica gel chromatography (ethylacetate eluent) to give 126 mg (55%) of the title compound as a whitesolid. mp 221°-223°. FDMS: m/e=355. α[D]₅₈₉ =+73.58 (c=1.06,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              84.47     84.63                                                H              7.09      7.06                                                 N              3.94      3.93                                                 ______________________________________                                    

EXAMPLE 72

(+)-(4aR)-(10bR)-4-methyl-8-(1-[2-methyl]naphthyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 2-methyl-1-naphthylboronic acid (182 mg, 0.98 mmol), 0.65 mLof 2M sodium carbonate solution and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24 h. The mixture was cooled, diluted with chloroform (50 mL) andwashed with brine (2×50 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent), to give 104 mg (44%) of the titlecompound as a white solid. mp 196°-200° . FDMS: m/e=369. α[D]₅₈₉ =+54.72(c=1.06, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              84.51     84.27                                                H              7.36      7.42                                                 N              3.79      3.93                                                 ______________________________________                                    

(+)-(4aR)-(10bR)-4-methyl-8-(2,3-dichlorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 2,3-dichlorophenylboronic acid (187 mg, 0.98 mmol), 0.65 mLof 2M sodium carbonate solution and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 16 h. The mixture was cooled, diluted with chloroform (50 mL) andwashed with brine (2×50 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent), to give 193 mg (79%) of the titlecompound as an off-white solid. mp 131°-134° FDMS: m/e=373 α[D]₅₈₉=+81.02 (c=1.05, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              67.39     68.46                                                H              5.65      5.70                                                 N              3.74      3.75                                                 ______________________________________                                    

EXAMPLE 74

(+)-(4aR)-(10bR)-4-methyl-8-(2-[N,N-diethylcarboxamido]-phenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one

A 15 mL round bottom flask was charged with(+-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 2-(N,N-diethylcarboxamido)phenylboronic acid (218 mg, 0.98mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fittedwith a reflux condenser, and the stirred mixture was heated at 80°,under nitrogen, for 24 h. The mixture was cooled, diluted withchloroform (50 mL) and washed with brine (2×25 mL). The combined organicextracts were dried over sodium sulfate, concentrated, and purified bysilica gel chromatography (ethyl acetate eluent), to give 180 mg (68%)of the title compound as a white solid. mp 147°-149° . FDMS: m/e=404α[D]₅₈₉ =+56.86 (c=1.02, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              77.19     76.99                                                H              7.97      8.05                                                 N              6.92      6.87                                                 ______________________________________                                    

EXAMPLE 75

(+)-(4aR)-(10bR)-4-methyl-8-(4-t-butylphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol),4-t-butylphenylboronic acid (139 mg, 0 .78 mmol), 0.65 mL of 2M sodiumcarbonate solution and 2 mL of THF, fitted with a reflux condenser, andthe stirred mixture was heated at 80°, under nitrogen, for 16 h. Themixture was cooled, diluted with chloroform (50 mL) and washed withbrine (2×25 mL). The combined organic extracts were dried over sodiumsulfate, concentrated, and purified by silica gel chromatography (ethylacetate eluent), to give 163 mg (69%) of the title compound as anamorphous solid. mp 141°-147° FDMS: m/e=361 α[D]₅₈₉ =+67.88 (c=1.05,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              83.06     83.34                                                H              8.64      8.72                                                 N              3.87      3.76                                                 ______________________________________                                    

EXAMPLE 76

(+)-(4aR)-(10bR)-4-methyl-8-(4-n-butylphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 4-n-butylphenylboronic acid (139 mg, 0 .78 mmol), 0.65 mL of2M sodium carbonate solution and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24 h. The mixture was cooled, diluted with chloroform (75 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent), to give 180 mg (77%) of the titlecompound as a white solid. mp 102°-108°. FDMS: m/e=361. α[D]₅₈₉ =+68.70(c=1.05, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              83.06     82.98                                                H              8.64      8.73                                                 N              3.87      3.64                                                 ______________________________________                                    

EXAMPLE 77

(+)-(4aR)-(10bR)-4-methyl-8-(3,4-dichlorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 3,4-dichlorophenylboronic acid (149 mg, 0.78 mmol), 0.65 mLof 2M sodium carbonate solution and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 16 h. The mixture was cooled, diluted with chloroform (75 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent) to give 156mg (64%) of the titlecompound as a foam. mp 129°-135°. FDMS: m/e=374. α[D]₅₈₉ =+68.66(c=1.03, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              67.39     68.37                                                H              5.65      5.81                                                 N              3.74      3.63                                                 ______________________________________                                    

EXAMPLE 78

(+)-(4aR)-(10bR)-4-methyl-8-(4-trifluoromethoxyphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 4-trifluoromethoxyphenylboronic acid (161 mg, 0.78 mmol),0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with areflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 24 h. The mixture was cooled, diluted with chloroform (50mL) and washed with brine (2×25 mL). The combined organic extracts weredried over sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent), to give 137 mg (56%) of the titlecompound as a waxy solid. FDMS: m/e=389. α[D]₅₈₉ =+48.95 (c=0.96,chloroform).

EXAMPLE 79

(+)-(4aR)-(10bR)-4-methyl-8-(4-trifluoromethylphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 4-trifluoromethylphenylboronic acid (148 mg, 0.78 mmol),0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with areflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 16 h. The mixture was cooled, diluted with chloroform (50mL) and washed with brine (2×25 mL). The combined organic extracts weredried over sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent), to give 137 mg (56%) of the titlecompound as a white solid. mp 86°-89°. FDMS: m/e=373 α[D]₅₈₉ =+28.90(c=1.04, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              70.76     70.96                                                H              5.94      6.00                                                 N              3.75      3.09                                                 ______________________________________                                    

EXAMPLE 80

(+)-(4aR)-(10bR)-4-methyl-8-(3-trifluoromethylphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol),tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol),3-trifluoromethylphenylboronic acid (148 mg, 0.78 mmol), 0.65 mL of 2Msodium carbonate solution and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24 h. The mixture was cooled, diluted with chloroform (75 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent), to give 180 mg (77%) of the titlecompound as an amorphous foam. mp 64°-87°. FDMS: m/e=373. α[D]₅₈₉ =64.42(c=1.04, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              70.76     71.04                                                H              5.94      5.98                                                 N              3.75      3.48                                                 ______________________________________                                    

EXAMPLE 81

(+)-(4aR)-(10bR)-4-methyl-8-(2-[6-methoxy]naphthyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 6-methoxynaphthyl-2-boronic acid (158 mg, 0.78 mmol), 0.65mL of 2M sodium carbonate solution and 2 mL of THF fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 17 h. The mixture was cooled, diluted with chloroform (75 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent), to give 233 mg (93%) of the titlecompound as a white solid. mp 216°-2°. FDMS: m/e=385. α[D]₅₈₉ =+59.64(c=0.97, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              81.01     80.72                                                H              7.06      6.99                                                 N              3.63      3.57                                                 ______________________________________                                    

EXAMPLE 82

(+)-(4aR)-(10bR)-4-methyl-8-(2-benzothienyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol),2-benzothiopheneboronic acid (140 mg, 0.78 mmol), 0.65 mL of 2M sodiumcarbonate solution and 2 mL of toluene, fitted with a reflux condenser,and the stirred mixture was heated at 80°, under nitrogen, for 17 h. Themixture was cooled, diluted with chloroform (75 mL) and washed withbrine (2×25 mL). The combined organic extracts were dried over sodiumsulfate, concentrated, and purified by silica gel chromatography (70%ethyl acetate/hexanes eluent), to give 190 mg (81%) of the titlecompound as a white solid. mp 247°-250°. FDMS: m/e=361. α[D]₅₈₉ =+93.33(c=0.36, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              76.42     76.29                                                H              6.41      6.37                                                 N              3.87      3.68                                                 ______________________________________                                    

EXAMPLE 83

(+)-(4aR)-(10bR)-4-methyl-8-(3,5-dimethylphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 3,5-dimethylphenylboronic acid (117 mg, 0.78 mmol), 0.65 mLof 2M sodium carbonate solution, 1.5 mL of toluene, and 1 mL ofmethanol, fitted with a reflux condenser, and the stirred mixture washeated at 80°, under nitrogen, for 24h. The mixture was cooled, dilutedwith dichloromethane (75 mL) and washed with brine (2×25 mL). Thecombined organic extracts were dried over sodium sulfate, concentrated,and purified by silica gel chromatography (ethyl acetate eluent), togive 186 mg (86%) of the title compound as a white solid. mp 129°-130°.FDMS: m/e =333. α[D]₅₈₉ =+73.31 (c=1.00, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              82.84     82.59                                                H              8.16      8.08                                                 N              4.20      4.01                                                 ______________________________________                                    

EXAMPLE 84

(+)-(4aR)-(10bR)-4-methyl-8- (4-biphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f ]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 4-biphenylboronic acid (154 mg, 0.78 mmol) ,0.65 mL of 2Msodium carbonate solution,l.5 mL of toluene, and 1 mL of methanol,fitted with a reflux condenser, and the stirred mixture was heated at80°, under nitrogen, for 24 h. The mixture was cooled, diluted withdichloromethane (75 mL) and washed with brine (2×25 mL). The combinedorganic extracts were dried over sodium sulfate, concentrated, andpurified by silica gel chromatography (ethyl acetate eluent), to give178 mg (72%) of the title compound as a white solid. mp 206°-207°. FDMS:m/e =381. α[D]₅₈₉ =+63.93 (c=1.01, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              85.00     84.51                                                H              7.13      6.85                                                 N              3.67      3.37                                                 ______________________________________                                    

EXAMPLE 85

(+)-(4aR)-(10bR)-4-methyl-8- (4-fluorophenyl)-10b-methyl-1, 2,3,4,4a,5,6,10b-octahydrobenzo [f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 4-fluorophenylboronic acid (109 mg, 0.78 mmol), 0.65 mL of2M sodium carbonate solution, 1.5 mL of toluene, and 1 mL of methanol,fitted with a reflux condenser, and the stirred mixture was heated at80°, under nitrogen, for 24 h. The mixture was cooled, diluted withdichloromethane (75 mL) and washed with brine (2×25 mL). The combinedorganic extracts were dried over sodium sulfate, concentrated, andpurified by silica gel chromatography (ethyl acetate eluent), to give140 mg (67%) of the title compound as a white solid. mp 121°-122°. FDMS:m/e=323. α[D]₅₈₉ =+79.46 (c=0.99, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              77.99     77.70                                                H              6.86      6.85                                                 N              4.33      4.25                                                 ______________________________________                                    

EXAMPLE 86

(+)-(4aR)-(10bR)-4-methyl-8-(3-nitrophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo [f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 3-nitrophenylboronic acid (130 mg, 0.78 mmol), 0.65 mL of 2Msodium carbonate solution, 1.5 mL of toluene, and 1 mL of methanol,fitted with a reflux condenser, and the stirred mixture was heated at80°, under nitrogen, for 24 h. The mixture was cooled, diluted withdichloromethane (75 mL) and washed with brine (2×25 mL). The combinedorganic extracts were dried over sodium sulfate, concentrated, andpurified by silica gel chromatography (ethyl acetate eluent), to give159 mg (70%) of the title compound as a tan solid. mp 181°-183° FDMS:m/e=350. α[D]₅₈₉ =+80.70 (c=1.04, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              71.98     71.85                                                H              6.33      6.22                                                 N              7.99      7.71                                                 ______________________________________                                    

EXAMPLE 87

(+)-(4aR)-(10bR)-4-methyl-8-(3,5-bis[trifluoromethyl]phenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol),3,5-bis(trifluoromethyl)phenylboronic acid (213 mg, 0.78 mmol), 0.65 mLof 2M sodium carbonate solution, 1.5 mL of toluene, and 1 mL ofmethanol, fitted with a reflux condenser, and the stirred mixture washeated at 80°, under nitrogen, for 24 h. The mixture was cooled, dilutedwith dichloromethane (75 mL) and washed with brine (2×25 mL). Thecombined organic extracts were dried over sodium sulfate, concentrated,and purified by silica gel chromatography (ethyl acetate eluent), togive 194 mg (68%) of the title compound as a white solid. mp 110°-112°.FDMS: m/e=441 α[D]₅₈₉ =+80.70 (c=1.05, methanol).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              62.58     62.43                                                H              4.79      4.81                                                 N              3.17      3.40                                                 ______________________________________                                    

EXAMPLE 88

(+)-(4aR)-(10bR)-4-methyl-8-(3-chloro-4-fluorophenyl)-b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo [f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 3-chloro-4-fluorophenylboronic acid (136 mg, 0.78 mmol),0.65 mL of 2M sodium carbonate solution, 1.5 mL of toluene, and 1 mL ofmethanol, fitted with a reflux condenser, and the stirred mixture washeated at 80°, under nitrogen, for 24 h. The mixture was cooled, dilutedwith dichloromethane (75 mL) and washed with brine (2×25 mL). Thecombined organic extracts were dried over sodium sulfate, concentrated,and purified by silica gel chromatography (ethyl acetate eluent), togive 170 mg (73%) of the title compound as a white solid. mp 114°-116°.FDMS: m/e=357. α[D]₅₈₉ =+86.00 (c=1.00, methanol).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              70.48     70.35                                                H              5.91      6.00                                                 N              3.91      3.95                                                 ______________________________________                                    

EXAMPLE 89

(+)-(4aR)-(10bR)-4-methyl-8-(4-[4-ethoxy]biphenyl)-b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 4-(4-ethoxy)biphenylboronic acid (189 mg, 0.78 mmol), 0.65mL of 2M sodium carbonate solution, 1.5 mL of toluene, and 1 mL ofmethanol, fitted with a reflux condenser, and the stirred mixture washeated am 80°, under nitrogen, for 24h. The mixture was cooled, dilutedwith dichloromethane (75 mL) and washed with brine (2×25 mL). Thecombined organic extracts were dried over sodium sulfate, concentrated,and purified by silica gel chromatography (ethyl acetate eluent), togive 166 mg (60%) of the title compound as a white solid. mp 177°-179°.FDMS: m/e=425. α[D]₅₈₉ =+66.30 (c=1.03, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              81.85     81.64                                                H              7.34      7.12                                                 N              3.29      3.57                                                 ______________________________________                                    

EXAMPLE 90

(+)-(4aR)-(10bR)-4-methyl-8-(3-aminophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 3-aminophenylboronic acid hemisulfate (181 mg, 0.78 mmol),1.0 mL of 2M sodium carbonate solution, 1.5 mL of toluene, and 1 mL ofmethanol, fitted with a reflux condenser, and he stirred mixture washeated at 80°, under nitrogen, for 24 h. The mixture was cooled, dilutedwith dichloromethane (75 mL) and washed with brine (2×25 mL). Thecombined organic extracts were dried over sodium sulfate, concentrated,and purified by silica gel chromatography (ethyl acetate eluent), togive 170 mg (82%) of the title compound as a tan solid. mp 230°-231°(decomp.) FDMS: m/e=320. α[D]₅₈₉ =+80.00 (c=1.05, methanol ).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              78.71     78.99                                                H              7.55      7.55                                                 N              8.74      9.12                                                 ______________________________________                                    

EXAMPLE 91

(+)-(4aR)-(10bR)-4-methyl-8-[3-([5-dimethylamino-1-naphthyl]sulfonylamino)phenyl]-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(83 mg, 0.27 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 3-dansylaminophenylboronic acid (99 mg, 0.27 mmol), 0.3 mLof 2M sodium carbonate solution, 0.5 mL of toluene, and 0.1 mL ofmethanol, fitted with a reflux condenser, and the stirred mixture washeated at 80°, under nitrogen, for 24 h. The mixture was cooled, dilutedwith dichloromethane (75 mL) and washed with brine (2×25 mL). Thecombined organic extracts were dried over sodium sulfate, concentrated,and purified by silica gel chromatography (ethyl acetate eluent), togive 94 mg (63%) of the title compound as a yellow solid. mp 130°-140°(decomp.) FDMS: m/e=553. α[D]₅₈₉ =+3.01 (c=1.03 methanol).

EXAMPLE 92

(+)-(4aR)-(10bR)-8-(1-naphthyl)-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (500 mg, 1.70 mmol), tetrakis(triphenylphosphine)palladium (0) (80 mg, 0.07 mmol), 1-napthylboronic acid (439 mg, 2.55mmol), 2.4 mL of 2M sodium carbonate and 4 mL of toluene, fitted with areflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 24 h. The mixture was cooled, diluted with dichloromethane(200 mL) and washed with brine (2×50 mL). The combined organic extractswere dried over sodium sulfate, concentrated, and purified by silica gelchromatography (0-50% methanol/ethyl acetate eluent gradient) to give405 mg (70%) of the title compound as a white solid. mp 247°-248°. FDMS:m/e=341. α[D]₅₈₉ =+1.93 (c=1.04, methanol).

EXAMPLE 93

(+)-(4aR)-(10bR)-8-(3-nitrophenyl)-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(500 mg, 1.70 mmol), tetrakis(triphenylphosphine) palladium (0) (80 mg,0.07 mmol), 3-nitrophenylboronic acid (426 mg, 2.55 mmol), 2.4 mL of 2Msodium carbonate and 4 mL of toluene, fitted with a reflux condenser,and the stirred mixture was heated at 80°, under nitrogen, for 24 h. Themixture was cooled, diluted with dichloromethane (200 mL) and washedwith brine (2×50 mL). The combined organic extracts were dried oversodium sulfate, concentrated, and purified by silica gel chromatography(ethyl acetate eluent) to give 456 mg (80%) of the title compound as awhite solid. mp 223°-225°. FDMS: m/e=336. α[D]₅₈₉ =+45.63 (c=1.03,methanol).

EXAMPLE 94

(+)-(4aR)-(10bR)-4-methyl-8-(2,4-dichlorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg,0.02 mmol), 2,4-dichlorophenylboronic acid (149 mg, 0.78 mmol), 0.65 mLof 2M sodium carbonate solution and 1.5 mL of toluene fitted with areflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 24 h. The mixture was cooled, diluted with dichloromethane(75 mL) and washed with brine (2×25 mL). The combined organic extractswere dried over sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent), followed by recrystallizationfrom ethyl acetate to give 157 mg (65%) of the title compound as anamorphous foam. mp 45°-48°. FDMS: m/e=374.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              67.39     66.95                                                H              5.65      5.43                                                 N              3.74      3.82                                                 ______________________________________                                    

The following group of examples illustrate alkylations, other than thepreferred alkylations of Examples 1-4 above, which provide modificationsof the benzoquinolinone nucleus.

EXAMPLE 95

(+)-(4aR)-(10bR)-4,10b-dimethyl-8-(4-chlorophenylthio)-1,2,3,4,-4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 350 mg portion of(4aR)-(10bR)-10b-methyl-8-(4-chlorophenylthio)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-onewas slurried in 14 ml of t-butanol in a nitrogen-blanketed flask, and0.2 ml of a 25 mg/ml aqueous solution of methyl iodide was added,followed by 330 mg of potassium t-butoxide. The mixture was stirred atambient temperature for 5 hours, and then the reaction mixture waspoured into water, and the mixture was extracted twice with ethylacetate. The combined organic layers were washed with water and withbrine, dried over sodium sulfate and concentrated under vacuum to obtainan oil, which was purified by silica gel chromatography on aChromatotron (Harrison Research Co.), using dichloromethane containingfrom 1% to 3% of methanol as the eluent. The product-containingfractions were combined and concentrated under vacuum to obtain 330 mgof solid, which was crystallized from heptane/ethyl acetate to obtain254 mg of the desired product. mp 122°-124° FDMS: m/e=371. α[D]₅₈₉=+60.2, α[D]₃₆₅ =+262.55 (chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              67.82     68.05                                                H              5.96      6.00                                                 N              3.77      3.89                                                 ______________________________________                                    

EXAMPLE 96

(+)-(4aR)-(10bR)-4,10b-dimethyl-8-(4-methylphenylthio) -1,2,3,4,4a,5,6,10b-octahydrobenzo [f]quinolin-3-one

Following the process of Example 95 a 390 mg portion of(4aR)-10bR)-10b-methyl-8-(4-methylphenylthio)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one was methylated to obtain 280 mg ofthe desired product. mp 154°-156° FDMS: m/e=351. α[D]₅₈₉ =+76.6, α[D]₃₆₅=+282.53 (chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              75.17     74.95                                                H              7.17      7.25                                                 N              3.99      4.17                                                 ______________________________________                                    

EXAMPLE 97

(+)-(4aR)-(10bR)-4,10b-dimethyl-8-(phenylsulfonyl)-1,2,3,4,-4a,5,6,10b-octahydrobenzo [f]quinolin-3-one

A 200 mg portion of(4aR)-(10bR)-10b-methyl-8-(phenylsulfonyl)-1,2,3,4,4a,5,6,10b-octahydrobenzo If]-quinolin-3-one was methylated with methyliodide to obtain 144 mg of the desired product. mp 165°-167° FDMS:m/e=369. α[D]₅₈₉ =+76.2, α[D]₃₆₅ =+269.7 (chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              68.27     68.44                                                H              6.27      6.39                                                 N              3.79      3.69                                                 ______________________________________                                    

EXAMPLE 98

(+)-(4aR)-(10bR)-4,10b-dimethyl-8-(2-naphthylthio)-1,2,3,4,-4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 282 mg portion of(4aR)-(10bR)-10b-methyl-8-(2-naphthylthio)-1,2,3,4,4a,5,6,10b-octahydrobenzo [f]quinolin-3-one was methylated with methyliodide following the process of Example 95 to obtain 137 mg of thedesired product. mp 138°-139.5° FDMS: m/e=387. α[D]₅₈₉ =+69.6, α[D]₃₆₅=+261.4 (chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              77.48     77.28                                                H              6.50      6.63                                                 N              3.61      3.71                                                 ______________________________________                                    

EXAMPLE 99

(+)-(4aR)-(10bR)-4,10b-dimethyl-8-(2-chlorophenylthio) -1,2,3,4,-4a,5,6,10b-octahydrobenzo [f]quinolin-3-one

The process of Example 95 was used to methylate 620 mg of(4aR)-(10bR)-10b-methyl-8-(2-chlorophenylthio)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one, to obtain 420 mg of the desiredproduct. mp 123°-125° FDMS: m/e=371. α[D]₅₈₉ =+76.0, α[D]₃₆₅ =+255.3(chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              67.82     67.87                                                H              5.96      5.97                                                 N              3.77      3.94                                                 ______________________________________                                    

EXAMPLE 100

(+)-(4aR)-(10bR)-4,10b-dimethyl-8-(3-chlorophenylthio)-1,2,3,4,-4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 612 mg portion of(4aR)-(10bR)-10b-methyl-8-(3-chlorophenylthio)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-onewas methylated with methyl iodide substantially as shown in Example 95.Attempts at crystallization of the product were unsuccessful, so it wascharacterized as an opaque colorless oil, 525 mg. FDMS: m/e=371. α[D]₅₈₉=+72.9, α[D]₃₆₅ =+265.2 (chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              67.82     67.60                                                H              5.96      5.91                                                 N              3.77      3.86                                                 ______________________________________                                    

EXAMPLE 1070

(+)-(4aR)-(10bR)-4,10b-dimethyl-8-(2-methylphenylthio) -1,2,3,4,-4a,5,6,10b-octahydrobenzo [f]quinolin-3-one

A 390 mg portion of(4aR)-(10bR)-10b-methyl-8-(2-methylphenylthio)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-onewas methylated substantially as shown in Example 95 above, to obtain 330mg of the desired product. mp 105°-106° FDMS: m/e=351. α[D]₅₈₉ =+77.0,α[D]₃₆₅ =+282.8 (chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              75.17     75.46                                                H              7.17      7.34                                                 N              3.98      3.95                                                 ______________________________________                                    

EXAMPLE 102

(+)-(4aR)-(10bR)-4,10b-dimethyl-8-(3-methylphenylthio) -1,2,3,4,-4a,5,6,10b-octahydrobenzo If]quinolin-3-one

A 380 mg portion of(4aR)-(10bR)-10b-methyl-8-(3-methylphenylthio)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-onewas methylated as shown in Example 95 above to obtain 290 mg of thedesired product. mp 103°-104° FDMS: m/e=351. α[D]₅₈₉ =+80.3, α[D]₃₆₅=+292.2 (chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              75.17     75.40                                                H              7.17      7.19                                                 N              3.98      3.98                                                 ______________________________________                                    

EXAMPLE 103

(+)-(4aR)-(10bR)-4,10b-dimethyl-8-(1-naphthylthio)-1,2,3,4,-4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 390 mg portion of(4aR)-(10bR)-10b-methyl-8-(1-naphthylthio)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onewas methylated as described in Example 95 above to obtain 300 mg of thedesired product. mp 161°-162° FDMS: m/e=387. α[D]₅₈₉ =+65.2, α[D]₃₆₅=+248.4 (chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              77.48     77.64                                                H              6.50      6.54                                                 N              3.61      3.54                                                 ______________________________________                                    

EXAMPLE 104

(+)-(4aR)-(10bR)-4,10b-dimethyl-8-(2-methoxyphenylthio)-1,2,3,4,-4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 430 mg portion of(4aR)-(10bR)-10b-methyl-8-(2-methoxyphenylthio)-1,2,3,4,44,5,6,10b-octahydrobenzo[f]-quinolin-3-onewas methylated substantially as described in Example 95 above to obtain300 mg of the desired product. mp 166°-167.5° FDMS: m/e=367. α[D]₅₈₉=+72.7, α[D]₃₆₅ =+265.1 (chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              71.90     71.98                                                H              6.86      6.64                                                 N              3.81      3.67                                                 ______________________________________                                    

EXAMPLE 105

(+)-(4aR)-(10bR)-4,10b-dimethyl-8-(4-methoxyphenylthio) -1,2,3,4,-4a,5,6,10b-octahydrobenzo [f]quinolin-3-one

A 480 mg portion of (4aR)-(10bR)-10b-methyl-8-(4-methoxyphenylthio)-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f]-quinolin-3-one was methylated asdescribed in Example 95 to obtain 400 mg of the desired product. mp150°-151° FDMS: m/e=367. α[D]₅₈₉ =+74.1, α[D]₃₆₅ =+276.8 (chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              71.90     71.95                                                H              6.86      6.64                                                 N              3.81      3.85                                                 ______________________________________                                    

EXAMPLE 106

(4aR)-(10bR)-4,10b-dimethyl-8-(3-quinolinylthio)-1,2,3,4,-4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 256 mg portion of(4aR)-(10bR)-10b-methyl-8-(3-quinolinylthio)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-onewas methylated according to the process of Example 95 to obtain 255 mgof the desired product, as an amorphous solid. FDMS: m/e=388.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              74.19     73.94                                                H              6.23      6.41                                                 N              7.21      7.13                                                 ______________________________________                                    

EXAMPLE 107

(+)-(4aR)-(10bR)-4,10b-dimethyl-8-(2-quinolinylthio)-1,2,3,4,-4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 420 mg portion of (4aR)-(10bR)-10b-methyl-8-(2-quinolinylthio)-1,2,3,4,4a, 5,6,10b-octahydrobenzo[f]-quinolin-3-one was methylated asdescribed in Example 95 to obtain 300 mg of the desired product. mp175°-177° FDMS: m/e=388. α[D]₅₈₉ =+65.9, α[D]₃₆₅ =absorbance(chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              74.19     74.01                                                H              6.23      6.10                                                 N              7.21      7.39                                                 ______________________________________                                    

EXAMPLE 108

(+)-(4aR)-(10bR)-4,10b-dimethyl-8-(2-fluorophenylthio) -1,2,3,4,-4a,5,6,10b-octahydrobenzo [f]quinolin-3-one

A 490 mg portion of(4aR)-(10bR)-10b-methyl-8-(2-fluorophenylthio)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one was methylated substantiallyaccording to the process of Example 95 to obtain 490 mg of the desiredproduct, which was not crystalline. mp 100°-103° FDMS: m/e=354. α[D]₅₈₉=+76.5, α[D]₃₆₅ =+273.6 (chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              70.96     71.21                                                H              6.24      6.32                                                 N              3.94      4.16                                                 ______________________________________                                    

EXAMPLE 109

(+)-(4aR)-(10bR)-4,10b-dimethyl-8-(3-fluorophenylthio) -1,2,3,4,-4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 460 mg portion of(4aR)-(10bR)-10b-methyl-8-(3-fluorophenylthio)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-onewas methylated according to the process of Example 95 to obtain 430 mgof the desired product in the form of an oil. FDMS: m/e=355. α[D]₅₈₉=+76.5, α[D]₃₆₅ =+275.2 (chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              70.96     71.11                                                H              6.24      6.32                                                 N              3.94      3.98                                                 ______________________________________                                    

EXAMPLE 110

(4aR)-(10bR)-4,10b-dimethyl-8-(8-quinolinylthio)-1,2,3,4,-4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 305 mg portion of(4aR)-(10bR)-10b-methyl-8-(8-quinolinylthio)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-onewas methylated substantially according to the process of Example 95 toobtain 114 mg of the desired product. mp 241-°242° FDMS: m/e=388.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              74.19     73.98                                                H              6.23      6.15                                                 N              7.21      7.18                                                 ______________________________________                                    

EXAMPLE 111

(+)-(4aR)-(10bR)-4,10b-dimethyl-8-(2-pyridinylthio)-1,2,3,4,-4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

Four hundred mg of(4aR)-(10bR)-10b-methyl-8-(2-pyridinylthio)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one was methylated substantiallyaccording to the process of Example 95 to obtain 330 mg of the desiredproduct. mp 174°-176° FDMS: m/e=338. α[D]₅₈₉ =+79.8, α[D]₁₆₅ =+288.7(chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              70.97     70.70                                                H              6.55      6.74                                                 N              8.28      8.06                                                 ______________________________________                                    

EXAMPLE 112

(4aR)-(10bR)-4,10b-dimethyl-8-(2-benzothiazolylthio)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 170 mg portion of(4aR)-(10bR)-10b-methyl-8-(2-benzothiazolylthio)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-onewas alkylated with methyl iodide substantially according to the processof Example 95 to obtain 84 mg of the desired product. mp 188°-189° FDMS:m/e=394.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              66.97     66.73                                                H              5.62      5.65                                                 N              7.10      6.87                                                 ______________________________________                                    

EXAMPLE 113

(4aR)-(10bR)-4,10b-dimethyl-8-(1-isoquinolinylthio)-1,2,3,4,-4a,5,6,10b-octahydrobenzo[f]quinolin-3-one A 140 mg portion of(4aR)-(10bR)-10b-methyl-8-(1-isoquinolinylthio)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-onewas methylated substantially according to the process of Example 95 toobtain 90 mg of the desired product. mp 196°-199° FDMS: m/e=388.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              74.19     74.08                                                H              6.23      6.41                                                 N              7.21      7.45                                                 ______________________________________                                    

EXAMPLE 114

(4aR)-(10bR)-4,10b-dimethyl-8-(4-isoquinolinylthio)-1,2,3,4,-4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 300 mg portion of(4aR)-(10bR)-10b-methyl-8-(4-isoquinolinylthio)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-onewas alkylated substantially according to the process of Example 95 toobtain 140 mg of the desired product. mp 161°-163° FDMS: m/e=388.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              74.19     74.05                                                H              6.23      6.18                                                 N              7.21      7.47                                                 ______________________________________                                    

EXAMPLE 115

(+)-(4aR)-(10bR)-4,10b-dimethyl-8-(4-pyridinylthio)-1,2,3,4,-4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 390 mg portion of(4aR)-(10bR)-10b-methyl-8-(4-pyridinylthio)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-onewas methylated substantially according to the process of Example 95 toobtain 228 mg of the desired product. mp 157°-158° FDMS: m/e=338.α[D]₅₈₉ =+77.5, α[D]₃₆₅ =absorbance (chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              70.97     71.25                                                H              6.55      6.27                                                 N              8.28      8.27                                                 ______________________________________                                    

EXAMPLE 116

(4aR)-(10bR)-4,10b-dimethyl-8-phenylthio-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

Potassium t-butoxide (0.22 g, 1.9 mmol) was added to 5 mL of t-butanolin a 25 mL round bottom flask. The(4aR)-(10bR)-10b-methyl-8-phenylthio-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one,(0.183 g, 0.566 mmol) was added followed by methyl iodide while coolingbriefly in an ice bath. The mixture was allowed to stir at roomtemperature for 18 h before diluting with ethyl acetate and filtering toremove inorganics. Filtrate was concentrated in vacuo to give a oilwhich was triturated in hexane/diethyl ether to facilitatecrystallization. Recrystallization from ethyl acetate/hexane gave 0.90 gof white crystals: mp 109°--112°. FD MS 337M+. Calcd for C₂₁ H₂₃ N₁ O₁S₁.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              74.74     74.55                                                H              6.87      6.79                                                 N              4.15      4.35                                                 ______________________________________                                    

EXAMPLE 117

(+)-(4aR)-(10bR)-4-methyl-8-(1-naphthyl)-10b-methyl-3,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-8-(1-naphthyl)-10b-methyl-3,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one(22 mg, 0.065 mmol), 0.20 mL of t-butanol, and potassium t-butoxide (22mg, 0.19 mmol). Methyl iodide (0.012 mL, 0.19 mmol) was added and themixture was stirred at room temperature for 4 h. The mixture was dilutedwith ethyl acetate, and purified by silica gel chromatography (ethylacetate eluent) to give 16 mg (70%) of the title compound as a yellowsolid, upon trituration from diethyl ether/hexanes. mp 172°-173°. FDMS:m/e=353.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              84.92     84.70                                                H              6.56      6.29                                                 N              3.96      3.55                                                 ______________________________________                                    

EXAMPLE 118

(+)-(4aR)-(10bR)-4-methyl-8-(3-nitrophenyl)-10b-methyl-3,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-4aR)-(10bR)-8-(3-nitrophenyl)-10b-methyl-3,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one(12 mg, 0.034 mmol), 0.10 mL of t-butanol, and potassium t-butoxide (12mg, 0.10 mmol). Methyl iodide (0.006 mL, 0.10 mmol) was added and themixture was stirred at room temperature for 4 h. The mixture was dilutedwith ethyl acetate, and purified by silica gel chromatography (ethylacetate eluent) to give 9 mg (75%) of the title compound as a whitesolid, upon trituration from diethyl ether/hexanes. mp 175°-177°. FDMS:m/e=348.

EXAMPLE 119

(+)-(4aR)-(10bR)-4-methyl-8-(4-nitrophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-8-(4-nitrophenyl)-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(14 mg, 0.04 mmol), 0.10 mL of t-butanol, and potassium t-butoxide (14mg, 0.12 mmol). Methyl iodide (0.03 mL, 0.08 mmol) was added and themixture was stirred at room temperature for 4 h. The mixture was dilutedwith ethyl acetate, and purified by silica gel chromatography (ethylacetate eluent) to give 10 mg (70%) of the title compound as a whitesolid. mp 59°-60°. FDMS: m/e=350.

EXAMPLE 120

(+)-(4aR)- <10bR)-4-methyl-8-(4-methylthiophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-4aR)-(10bR)-8-(4-methylthiophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(20 mg, 0.06 mmol), 0.10 mL of t-butanol, and potassium t-butoxide (20mg, 0.18 mmol). Methyl iodide (0.011 mL, 0.18 mmol) was added and themixture was stirred at room temperature for 4 h. The mixture was dilutedwith ethyl acetate, and purified by silica gel chromatography (ethylacetate eluent) to give 15 mg (72%) of the title compound as a whitesolid. mp 115°-117°. FDMS: m/e=351.

EXAMPLE 121

(+)-(4aR)-(10bR)-4-methyl-8-(4-cyanophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-8-(4-cyanophenyl)-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(24 mg, 0.08 mmol), 0.20 mL of n-butanol, and potassium t-butoxide (26mg, 0.24 mmol). Methyl iodide (0.014 mL, 0.24 mmol) was added and themixture was stirred at room temperature for 4 h. The mixture was dilutedwith ethyl acetate, and purified by silica gel chromatography ethylacetate eluent) to give 20 mg (80%) of the title compound as a whitesolid. mp 148°-150°. FDMS: m/e=330.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              79.97     79.77                                                H              6.71      6.63                                                 N              8.48      8.69                                                 ______________________________________                                    

EXAMPLE 122

(+)-(4aR)-(10bR)-4-methyl-8-(4-[isopropylcarbonyl]phenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-8-(4-acetylphenyl)-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(33 mg, 0.10 mmol), 0 .25 mL of t-butanol, and potassium t-butoxide (33mg, 0.33 mmol ). Methyl iodide (0.019 mL, 0.33 mmol) was added and themixture was stirred at room temperature for 4 h. The mixture was dilutedwith ethyl acetate, and purified by silica gel chromatography (ethylacetate eluent) to give 20 mg (54%) of the title compound as a whitesolid. mp 101°-103° FDMS: m/e=375.

EXAMPLE 123

(+)-(4aR)-(10bR)-4-methyl-8-(4-methylsulfonamidophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-8-(4-sulfonamidophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(33 mg, 0.09 mmol), 0.20 mL of t-butanol, and potassium t-butoxide (30mg, 0.27 mmol). Methyl iodide (0.017 mL, 0.27 mmol) was added and themixture was stirred at room temperature for 4 h. The mixture was dilutedwith ethyl acetate, and purified by silica gel chromatography (ethylacetate eluent) to give 20 mg (56%) of the title compound as an oil.FDMS: m/e=398.

EXAMPLE 124

(+)-(4aR)-(10bR)-4-methyl-8-(2-nitrophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-8-(2-nitrophenyl)-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(60 mg, 0.18 mmol), 0.3 mL of t-butanol, and potassium t-butoxide (60mg, 0.54 mmol). Methyl iodide (0.034 mL, 0.54 mmol) was added and themixture was stirred at room temperature for 4 h. The mixture was dilutedwith ethyl acetate, and purified by silica gel chromatography (ethylacetate eluent) to give 50 mg (80%) of the title compound as a whitesolid. mp 130°-131°. FDMS: m/e=350.

EXAMPLE 125

(+)-(4aR)-(10bR)-4-methyl-8-(2-cyanophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-8-(2-cyanophenyl)-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (55 mg, 0.17 mmol ) , 0.4 mL oft-butanol, and potassium t-butoxide (58 mg, 0.51 mmol). Methyl iodide(0.034 mL, 0.54 mmol) was added and the mixture was stirred at roomtemperature for 4 h. The mixture was diluted with ethyl acetate, andpurified by silica gel chromatography (ethyl acetate eluent) to give 50mg (87%) of the title compound as a white solid. mp 54°-55°. FDMS:m/e=330. α[D]₅₈₉ =+74.33 (c=0.36, chloroform).

EXAMPLE 126

(+)-(4aR)-(10bR)-4-methyl-8-(2-[5-(phenoxymethyl)thienyl])-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-8-(2-[5-(phenoxymethyl)thienyl])-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (70 mg, 0.17 mmol), 0.4 mL oft-butanol, and potassium t-butoxide (58 mg, 0.51 mmol). Methyl iodide(0.034 mL, 0.54 mmol) was added and the mixture was stirred at roomtemperature for 4 h. The mixture was diluted with ethyl acetate, andpurified by silica gel chromatography (ethyl acetate eluent) to give 65mg (90%) of the title compound as a white solid. mp 149°-151°. FDMS:m/e=417 α[D]₅₈₉ =+68.50 (c=0.89, chloroform).

EXAMPLE 127

(+)-(4aR)-(10bR)-4-methyl-8-(2-methylthiophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-8-(2-methylthiophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(55 mg, 0.16 mmol), 0.4 mL of t-butanol, and potassium t-butoxide (55mg, 0.48 mmol). Methyl iodide (0.031 mL, 0.48 mmol) was added and themixture was stirred at room temperature for 4 h. The mixture was dilutedwith ethyl acetate, and purified by silica gel chromatography (ethylacetate eluent) to give 15 mg (26%) of the title compound as an oil.FDMS: m/e=351.

EXAMPLE 128

(+)-(4aR)-(10bR)-4-methyl-8-(2,4,5-trifluorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-8-(2,4,5-trifluorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (43 mg, 0.12 mmol), 0.3 mL oft-butanol, and potassium t-butoxide (42 mg, 0.36 mmol). Methyl iodide(0.023 mL, 0.36 mmol) was added and the mixture was stirred at roomtemperature for 4 h. The mixture was diluted with ethyl acetate, andpurified by silica gel chromatography (ethyl acetate eluent) to give 40mg (89%) of the title compound as a foam. FDMS: m/e=359.

EXAMPLE 129

(+)-(4aR)-(10bR)-4-methyl-8-(2-[5-(4-fluorophenoxymethyl)-thienyl])-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-10bR)8-(2-[5-(4-fluorophenoxymethyl)thienyl])-10b-methyl1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(47 mg, 0.11 mmol), 0.3 mL of t-butanol, and potassium t-butoxide (38mg, 0.33 mmol). Methyl iodide (0.021 mL, 0.33 mmol) was added and themixture was stirred at room temperature for 4 h. The mixture was dilutedwith ethyl acetate, and purified by silica gel chromatography (ethylacetate eluent) to give 35 mg (71%) of the title compound as a whitesolid. mp 136°-138°. FDMS: m/e=435 α[D]₅₈₉ =+63.40 (c=0.74, chloroform).

EXAMPLE 130

(+)-(4aR)-<10bR)-4-methyl-8-(2,3,5-trifluorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-8-(2,3,5-trifluorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (35 mg, 0.10 mmol), 0.3 mL oft-butanol, and potassium t-butoxide (34 mg, 0.30 mmol). Methyl iodide(0.019 mL, 0.30 mmol) was added and the mixture was stirred at roomtemperature for 4 h. The mixture was diluted with ethyl acetate, andpurified by silica gel chromatography (ethyl acetate eluent) to give 30mg (83%) of the title compound as a foam. FDMS: m/e=359.

EXAMPLE 131

(+)-(4aR)-(10bR)-4-methyl-8-(2-fluorenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-8-(2-fluorenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(31 mg, 0.08 mmol), 0.2 mL of t-butanol, and potassium t-butoxide (27mg, 0.24 mmol). Methyl iodide (0.015 mL, 0.24 mmol) was added and themixture was stirred at room temperature for 4 h. The mixture was dilutedwith ethyl acetate, and purified by silica gel chromatography ethylacetate eluent/ to give 26 mg (82%) of the title compound as anoff-white solid. mp 175° (decomp). FDMS: m/e=393.

EXAMPLE 132

(+)-(4aR)-<10bR)-4-methyl-8-(3-[2,5-dichlororo]thienyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-10bR)-8-(3-[2,5-dichloro]thienyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (49 mg, 0.13 mmol), 0.4 mL oft-butanol, and potassium t-butoxide (45 mg, 0.39 mmol). Methyl iodide(0.025 mL, 0.39 mmol) was added and the mixture was stirred at roomtemperature for 4 h. The mixture was diluted with ethyl acetate, andpurified by silica gel chromatography (ethyl acetate eluent) to give 35mg (69%) of the title compound as an oil. FDMS: m/e=379.

EXAMPLE 133

(+)-(4aR)-(10bR)-4-methyl-8-(4-nitro-2-trifluoromethyl-phenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-10bR)-8-(4-nitro-2-trifluoromethylphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (48 mg, 0.12 mmol), 0.3 mL oft-butanol, and potassium t-butoxide (40 mg, 0.36 mmol). Methyl iodide !0.022 mL, 0.36 mmol) was added and the mixture was stirred at roomtemperature for 4 h. The mixture was diluted with ethyl acetate, andpurified by silica gel chromatography (ethyl acetate eluent) to give 35mg (70%) of the title compound as a white solid. mp 128°-130°. FDMS:m/e=418.

EXAMPLE 134

(+)-(4aR)-(10bR)-4-methyl-8-(2-nitro-4-trifluoromethyl-phenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-8-(2-nitro-4-trifluoromethylphenyl )-10b-methyl-1,2,3,4, 4a, 5,6,10b-octahydrobenzo[f]quinolin-3-one (48 mg, 0.12mmol), 0.3 mL of t-butanol, and potassium t-butoxide (40 mg, 0.36 mmol).Methyl iodide (0.022 mL, 0.36 mmol) was added and the mixture wasstirred at room temperature for 4 h. The mixture was diluted with ethylacetate, and purified by silica gel chromatography (ethyl acetateeluent) to give 38 mg (76%) of the title compound as an off- whitesolid. mp 55°-57°. FDMS: m/e =418. α[D]₅₈₉ =+60.50 (c=0.16, methanol).

EXAMPLE 135

(+)-(4aR)-(10bR)-4-methyl-8-(4-chloro-2,3,5,6-tetrafluoro-phenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-8-(4-chloro-2,3,5,6-tetrafluorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(43 mg, 0.12 mmol), 0.3 mL of t-butanol, and potassium t-butoxide (40mg, 0.36 mmol). Methyl iodide (0,022 mL, 0.36 mmol) was added and themixture was stirred at room temperature for 4 h. The mixture was dilutedwith ethyl acetate, and purified by silica gel chromatography (ethylacetate eluent) to give 30 mg (66%) of the title compound as anoff-white solid. mp 150°-151°. FDMS: m/e=412 α[D]₅₈₉ =+68.57 (c=0.12,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              61.25     61.04                                                H              4.41      4.53                                                 N              3.40      3.22                                                 ______________________________________                                    

EXAMPLE 136

(4aR)-(10bR)-8-benzylthio-4,10b-dimethyl-1,2,3,4,4a,5,5,10b-octahydrobenzo[f]quinolin-3-one

A 275.2 mg portion of (4aR)-(10bR)-10b-methyl-8-benzylthio-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one was methylated substantiallyaccording to the process of Example 95. This material was purified on aChromatotron (2 mm plate, eluted with 3% methanol/chloroform) followedby recrystallization from ethyl acetate to give 150 mg of the desiredwhite solid (52% yield). mp 137°-138° FDMS: m/e=351. α[D]₅₈₉ =59.44(c=0.36 in methanol).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              75.17     74.90                                                H              7.17      7.34                                                 N              3.99      4.03                                                 ______________________________________                                    

EXAMPLE 137

(4aR)-(10bR)-8-phenylthiomethyl-4,10b-dimethyl-1,2,3,4,-4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 157 mg portion of(4aR)-(10bR)-10b-methyl-8-phenylthiomethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo [f]-quinolin-3-one was methylated substantiallyaccording to the process of Example 95. This material was purified on aChromatotron (2 mm plate, eluted with ethyl acetate) to give 134 mg ofthe desired white solid (82% yield). mp 144°-146°. FDMS: m/e=351.α[D]₅₈₉ =78.54 {c=0.5 in methanol).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              75.17     74.92                                                H              7.17      7.27                                                 N              3.98      4.19                                                 ______________________________________                                    

EXAMPLE 138

(4aR)-(10bR)-8-(2-benzothiazole)thiomethyl-4,10b-dimethyl-1, 2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 202 mg portion of(4aR)-(10bR)-10b-methyl-8-(2-benzothiazole)thiomethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onewas methylated substantially according to the process of Example 95.This material was purified on a Chromatotron (2 mm plate, eluted withethyl acetate) to give 158 mg of the desired white solid (76% yield). mp182°-184°. FDMS: m/e=408. α[D]₅₈₉ =67.31 (c=0.5 in methanol).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              67.61     67.74                                                H              5.92      6.03                                                 N              6.86      6.98                                                 ______________________________________                                    

EXAMPLE 139

(4aR)-(10bR)-8-diphenylmethyl-4,10b-dimethyl-1,2,3,4,4a5,6,10b-octahydrobenzo[f]quinolin-3-one

A 109 mg portion of (4aR)-(10bR)-10b-methyl-8-diphenylmethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one was methylated substantiallyaccording to the process of Example 95 above to obtain 109 mg of crudeproduct, which was purified by chromatography as shown in Example 95followed by recrystallization to obtain 33 mg of the desired product. mp145°-146°. FDMS: m/e=396. α[D]₅₈₉ =58.93 (c=0.5 in chloroform).

The following group of examples demonstrate oxidations which providehexahydroquinolinones in which the groups R and R¹ represent a bond.

Example 140

(+)-(4aR)-(10bR)-8-(1-naphthyl)-10b-methyl-3,4,4a, 5,6,10b-hexahydrobenzo [f]quinolin-3-one

To a suspension of(+)-(4aR)-(10bR)-8-(1-naphthyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one(295 mg, 0.865 mmol), in 3.5 mL of 1,4-dioxane was added DDQ (216 mg,1.1 equiv.) followed by bistrimethylsilyltrifluoromethyl acetamide (998mg, 4.5 equiv.), and the solution was stirred at room temperature for 2h, then heated at 100° for 20h. The mixture was cooled to roomtemperature, diluted with ethyl acetate, and washed with 2M sodiumhydroxide. The organic phase was washed with brine, dried over sodiumsulfate, concentrated and chromatographed on silica gel (ethyl acetateeluent) to give, after trituration from ether/hexanes, 60 mg (20%) ofthe title compound as a white solid. mp 199°-201° (decomp.) FDMSm/e=339. α[D]₅₈₉ =+35.98 (c=0.67, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              84.92     84.72                                                H              6.24      5.98                                                 N              4.13      3.85                                                 ______________________________________                                    

EXAMPLE 141

(+)-(4aR)-(10bR)-8-(3-nitrophenyl)-10b-methyl-3,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one

To a suspension of(+)-(4aR)-(10bR)-8-(3-nitrophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo If]-quinolin-3-one (264 mg, 0.786 mmol), in 3.0mL of 1,4-dioxane was added DDQ (196 mg, 1.1 equiv.) followed bybistrimethylsilyltrifluoromethyl acetamide (911 mg, 4.5 equiv.), and thesolution was stirred at room temperature for 2 h, then heated at 100°for 20 h. The mixture was cooled to room temperature, diluted with ethylacetate, and washed with 2M sodium hydroxide. The organic phase waswashed with brine, dried over sodium sulfate, concentrated andchromatographed on silica gel (ethyl acetate eluent) to give, aftertrituration from ether/hexanes, 55 mg (21%) of the title compound as anorange solid. mp 205°-206°. FDMS m/e=334. α[D]₅₈₉ =+57.23 (c=0.66,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              71.84     71.47                                                H              5.43      5.49                                                 N              8.38      7.96                                                 ______________________________________                                    

EXAMPLE 142

(+)-(4aR)- <10bR)-8-(3-isoquinolinyl) 10b-methyl-3,4,4a,5,6,10b-hexahydrobenzo[f]quinolin-3-one

To a suspension of(+)-(4aR)-(10bR)-8-(3-isoquinolinyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(80 mg, 0.230 mmol), in 1.0 mL of 1,4-dioxane was added DDQ (58 mg, 1.1equiv.) followed by bistrimethylsilyltrifluoromethyl acetamide (270 mg,4.5 equiv.), and the solution was stirred at room temperature for 2 h,then heated at 100° for 20 h. The mixture was cooled to roomtemperature, diluted with ethyl acetate, and washed with 2M sodiumhydroxide. The organic phase was washed with brine, dried over sodiumsulfate, concentrated and chromatographed on silica gel (ethyl acetateeluent) to give, after trituration from ether/hexanes, 18mg (24%) of thetitle compound as a white solid. mp 248° (decomp.) FDMS m/e=340.

Preparation 6

(4aR)-(10bR)-8-formyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

Methyllithium (1.5 mL, 2.1 mmol of a 1.4M solution in diethyl ether) wasadded to(4aR)-(10bR)-8-bromo-10b-methyl-1,2,3,4,-4a,5,6,10b-oczahydrobenzo[f]quinolin-3-one(0.500 g, 1.7 mmol) in 25 mL of anhydrous THF which had been cooled in adry ice/isopropanol bath under nitrogen, and was stirred for 15 minbefore addition of t-butyllithium (2.0 mL, 3.4 mmol of a 1.7M solutionin pentane). After 30 min, dimethylformamide (0.4 mL) was added, and themixture was allowed to warm to 0°, and additional dimethylformamide (0.2mL) was added. The ice bath was removed and the reaction was quenchedwith 1N hydrochloric acid to make pH=2, and then the mixture wasextracted with 10% isopropanol/chloroform. The combined organic extractswere washed well with water, dried over sodium sulfate, and evaporated.The resulting product was slurried in diethyl ether beforerecrystallizing from 50% ethyl acetate/hexane to give off-whitecrystals: mp 185°-189°. FD MS 243M+; Calcd for C₁₅ H₁₇ N₁ O₂ : C, 74.05;H, 7.04; N, 5.76. Found: C, 73.85; H, 7.11; N, 5.91.

Preparation 7

(4aR)-(10bR)-8-carboxy-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

In a flame-dried 3-neck round bottom flask equipped with magneticstirrer and nitrogen inlet was dissolved(4aR)-(10bR)-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline-3-one(500 mg, 1.7 mmol). The solution was cooled to -78° and treated withethereal methyllmthium (1.7 mL, 1.4M, 2.4 mmol) added dropwise over 2min. After further stirring for 15 min., a solution of c-butyllithium(2.9 mL, 1.7M in pentane, 5.0 mmol) was added dropwise. Followingcomplete addition, the suspension was treated with excess carbondioxide, (generated from dry ice, dried by passage through calciumsulfate) added subsurface for 2 min. The mixture was allowed to warm toambient temperature and was acidified with 1N aqueous hydrochloric acid.The mixture was extracted with 10% isopropanol/-chloroform and theorganic phase dried over anhydrous magnesium sulfate. Removal of solventunder reduced pressure afforded the crude product (520 mg) contaminatedwith pivalic acid. Trituration with ethyl acetate afforded product (322mg) as a white powder (mp (320°) m/e 259.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              69.48     69.51                                                H              6.61      6.63                                                 N              5.40      5.18                                                 ______________________________________                                    

EXAMPLE 143

(+)-(4aR)-(10bR)-4-methyl-8-(phenylcarboxamido)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 50 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-carboxy-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.37) and 2 mL of benzene. Oxalyl chloride (1.1 mmol) was addeddropwise via syringe to the stirred mixture, followed by a catalyticamount of dimethylformamide (one drop). Allowed to stir at roomtemperature for 25 min, then removed volatiles in vacuo. Added 1 mL ofTHF, followed by a solution of aniline and pyridine (4 eq) in 1 mL ofTHF to the acid chloride solution at 0°. Allowed to warm to roomtemperature. Diluted with 50 mL of chloroform, and washed with 1Nhydrochloric acid (2×25 mL), 10% aq. sodium bicarbonate (2×25 mL),water, (2×25 mL), and brine (2×25 mL). The combined organic extractswere dried over sodium sulfate, concentrated and chromatographed onsilica (ethyl acetate eluent), to give 24 mg (19%) of the title compoundas an amorphous yellow foam. FDMS: m/e=348.

EXAMPLE 144

(+)-(4aR)-(10bR)-4-methyl-8-benzyloxycarbonyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 50 mL round bottom flask was charged with(+)-{4aR)-(10bR)-4-methyl-8-carboxy-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.37) and 2 mL of benzene. Oxalyl chloride (1.1 mmol) was addeddropwise via syringe to the stirred mixture, followed by a catalyticamount of dimethylformamide (one drop). The mixture was allowed to stirat room temperature for 25 min, and then the volatiles were removed invacuo. One mL of THF was added, followed by a solution of benzyl alcoholand pyridine (4 eq) in 1 mL of THF at 0°. It was then allowed to warm toroom temperature, diluted with 50 mL of chloroform, and washed with 0.1Nhydrochloric acid (2×25 mL), 10% sodium bicarbonate (2×25 mL), water,(2×25 mL), and brine (2×25 mL. The combined organic extracts were driedover sodium sulfate, concentrated and chromatographed on silica (ethylacetate eluent), to give 11 mg (8%) of the title compound as anamorphous yellow foam. FDMS: m/e=349.

EXAMPLE 145

(+)-(4aR)-(10bR)-4-methyl-8-phenoxycarbonyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 50 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-carboxy-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(300 mg, 1.10 mmol) and 6 mL of benzene. Oxalyl chloride (3.3 mmol) wasadded dropwise via syringe to the stirred mixture, followed by acatalytic amount of dimethylformamide (two drops). It was allowed tostir at room temperature for 75 min. and then the volatiles were removedin vacuo. Four mL of THF was added, followed by a solution of phenol andpyridine (4 eq) in 2 mL of THF at 0°. It was allowed to warm to roomtemperature, diluted with 50 mL of ethyl acetate, and washed with 0.1Nhydrochloric acid (2×25 mL), 10% sodium bicarbonate (2×25 mL), water,(2×25 mL), and brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated and chromatographed on silica (0-2%methanol/dichloromethane gradient eluent), followed by additionalchromatography (80% ethyl acetate/hexanes eluent) to give 43 mg (11%) ofthe title compound as a yellow solid. mp 194°-196°. FDMS: m/e=349.α[D]₅₈₉ =+78.53 (c=1.00, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              75.62     75.44                                                H              6.63      6.74                                                 N              4.01      4.00                                                 ______________________________________                                    

EXAMPLE 146

(+)-(4aR)-(10bR)-4-methyl-8-(benzylcarboxamido)-10b-methyl-1, 2,3,4,4a,5,6,10b-octahydrobenzo [f]quinolin-3-one

A 50 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-carboxy-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.37) and 2 mL of benzene. Oxalyl chloride (1.1 mmol) was addeddropwise via syringe to the stirred mixture, followed by a catalyticamount of dimethylformamide (one drop). The mixture was stirred at roomtemperature for 25 min, and then the volatiles were removed in vacuo.One mL of THF was added, followed by a solution of benzylamine andpyridine (4 eq) in 1 mL of THF at 0°. It was allowed to warm to roomtemperature, diluted with 50 mL of chloroform, and washed with 1Nhydrochloric acid (2×25 mL), 10% aq. sodium bicarbonate (2×25 mL),water, (2×25 mL), and brine (2×25 mL). The combined organic extractswere dried over sodium sulfate, concentrated and chromatographed onsilica (ethyl acetate eluent), to give 40 mg (30%) of the title compoundas an amorphous brown foam. FDMS: m/e=362.

EXAMPLE 147

(4aR)-(10bR)-4,10b-dimethyl-8-diphenylmethoxycarbonyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

Under an atmosphere of nitrogen, 100 mg of4,10b-dimethyl-8-carboxy-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneand 66 mg of 1,1'-carbonyldiimidazole were dissolved in 5 mL ofanhydrous dimethylformamide and stirred for 1 h. Then 74 mg ofbenzhydrol was added, and the reaction was stirred for 18 hours, stillat ambient temperature. The volatiles were then removed under highvacuum, and the residue was dissolved in 50 mL of dichloromethane andwashed with 40 mL of 1N hydrochloric acid, with two 40 mL portions ofsaturated aqueous sodium bicarbonate, and finally with 40 mL of brine.The organic layer was dried with sodium sulfate, filtered and evaporatedunder vacuum to give 141 mg of impure product, which was purified bychromatography on silica gel, eluting with ethyl acetate to obtain 91 mg(57%) of the desired product. An analytical sample was recrystallizedfrom ethyl acetate/water. mp 130°-131°. FDMS: m/e=439.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              79.24     79.49                                                H              6.65      6.57                                                 N              3.19      3.28                                                 ______________________________________                                    

EXAMPLE 148

(4aR)-(10bR)-4,10b-dimethyl-8-diphenylmethyl-carboxamido-1,2,3,4,4a,5,6,10b-octahydrobenzo [f ]quinolin-3-one

A 150 mg portion of4,10b-dimethyl-8-carboxy-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-oneand 97.9 mg of 1,1'-carbonyldiimidazole were dissolved in 4 mL of drydimethylformamide. The reaction was stirred under nitrogen for 4 h atambient temperature, and then 108 μl of diphenylmethylamine was thenadded to the solution, and it was stirred for 36 h more. The mixture wasthen evaporated under high vacuum, and the residue was taken inchloroform and washed with 1N hydrochloric acid, twice with saturatedaqueous sodium bicarbonate, and finally with brine. The organic layerwas then dried, filtered and evaporated under vacuum to recover 246 mgof impure product. That product was purified on a Chromatotron, elutingwith ethyl acetate. The product-containing fraction was recrystallizedfrom ethyl acetate/hexane to obtain 94 mg (40%) of the desired product.mp 210°-211°. FDMS: m/e=438.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              79.42     79.27                                                H              6.89      6.99                                                 N              6.39      6.42                                                 ______________________________________                                    

The following preparation and example illustrates syntheses of compoundsmaking use of an SH-substituted benzoquinolinone nucleus compound.

Preparation 8

(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one

To a solution of(+)-(4aR)-(10bR)-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(5.88 g, 20 mmol) in 300 mL of anhydrous THF was added methyllithium(158 mL, 1.4M solution in diethyl ether) at -78°. The mixture wasallowed to stir at -78° for 20 min, then t-butyllithium (26 mL, 1.7M inpentane) was added. The mixture was stirred for an additional 90 min,and N,N-diisopropylthiuram disulfide (14.1 g, 40 mmol) in 80 mL ofanhydrous THF was added at -78°. The mixture was stirred for 15 min, thecold bath was removed, and the mixture was allowed to warm to roomtemperature. To the mixture was added 100 mL of 1N hydrochloric acid,the organic phase was separated and washed with 1N hydrochloric acid(200 mL), 10% sodium bicarbonate (2 X 200 mL), and brine (2×200 mL). Theorganic layer was dried over sodium sulfate, concentrated, and purifiedby silica gel chromatography (100% ethyl acetate -5% methanol/ethylacetate eluent gradient) to give 6.14 g (79%) of material which wasdissolved in 61 mL of t-butanol, and potassium t-butoxide (7.42 g, 62.8mmol) was added. The mixture was allowed to stir at room temp for 30 min(became homogeneous), cooled to 0°, and methyl iodide (62.8 mmol in 10mL of t-butanol) was added dropwise via addition funnel. The cold bathwas removed and the mixture was allowed to stir at room temperature for16 h. The mixture was then diluted with 300 mL of ethyl acetate, theorganic phase was separated, washed with brine, dried over sodiumsulfate and concentrated to give 6.08 g (96%) of(+)-(4aR)-10bR)-4-methyl-8-([N,N-diisopropyl]thiuramyl)-1,2,3,4,4a,5,6,1b-octahydrobenzo[f]-quinolin-3-one as a white solid. mp 181°-182°.FDMS m/e=404. α[D]₅₈₉ =+72.11 (c=0.21, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              65.30     65.11                                                H              7.97      7.96                                                 N              6.92      7.07                                                 ______________________________________                                    

The above thiuram (6.08 g, 15.0 mmol) was dissolved in 50 mL oftrifluoroacetic acid and heated at 72° for 16 h. The solution wascooled, the volatiles were removed via rotary evaporator, the resultingoil was dissolved in chloroform, and the organic layer was washed with10% sodium bicarbonate solution (2×200 mL) followed by brine (2×200 mL).The organic extract was dried over sodium sulfate, and concentrated togive 3.80 g (96%) of the title 8-mercapto compound as oil, used directlywithout further purification. FDMS m/e=261.

EXAMPLE 149

(+)-(4aR)-(10bR)-4-methyl-8-(2-thiazoylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo [f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol),2-bromothiazole (75 mg, 0.46 mmol) and 1 mL of anhydrousdimethylformamide, fitted with a reflux condenser, and the stirredmixture was heated at 60°, under nitrogen, for 18 h. The mixture wascooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (ethyl acetateeluent) to give 30 mg (23%) of the title compound as an amorphous solid.mp 140°-142°. FDMS: m/e=344.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              62.76     62.52                                                H              5.85      5.96                                                 N              8.13      7.93                                                 ______________________________________                                    

EXAMPLE 150

(+)-(4aR)-(10bR)-4-methyl-8-(2-benzoxazolylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol),2-chlorobenzoxazole (71 mg, 0.46 mmol) and 1.5 mL of anhydrousdimethylformamide, fitted with a reflux condenser, and the stirredmixture was heated at 60°, under nitrogen, for 18h. The mixture wascooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (ethyl acetateeluent) to give 65 mg (45%) of the title compound as an amorphous foam.FDMS: m/e=378.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              69.82     67.82                                                H              5.86      6.55                                                 N              7.40      7.15                                                 ______________________________________                                    

EXAMPLE 151

(+)-(4aR)-(10bR)-4-methyl-8-(2-pyrimidinylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol),2-chloropyrimidine (53 mg, 0.46 mmol) and 1 mL of anhydrousdimethylformamide, fitted with a reflux condenser, and the stirredmixture was heated at 60°, under nitrogen, for 18 h. The mixture wascooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (ethyl acetateeluent) to give 30 mg (23%) of the title compound as an oil. FDMS:m/e=339.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              67.23     67.55                                                H              6.24      5.88                                                 N              12.38     12.25                                                ______________________________________                                    

EXAMPLE 152

(+)-(4aR)-(10bR)-4-methyl-8-(2-pyrazinylthio)-10b-methyl-1, 2,3,4,4a,5,6,10b-octahydrobenzo [f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol),2-chloropyrazine (53 mg, 0.46 mmol) and 1 mL of anhydrousdimethylformamide, fitted with a reflux condenser, and the stirredmixture was heated at 60°, under nitrogen, for 18 h. The mixture wascooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (80% ethylacetate/hexanes eluent) to give 63 mg (49%) of the title compound as anoff white solid. mp 94°-95°. FDMS: m/e=339. α[D]₅₈₉ =+88.14 (c=0.92,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              67.23     67.26                                                H              6.24      6.04                                                 N              12.38     11.90                                                ______________________________________                                    

EXAMPLE 153

(+)-(4aR)-(10bR)-4-methyl-8-(2-quinoxalinylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo [f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassiumcarbonate (158 mg, 1.14 mmol), 2-chloroquinoxaline (76 mg, 0.46 mmol)and 1.5 mL of anhydrous dimethyl formamide, fitted with a refluxcondenser, and the stirred mixture was heated at 60°, under nitrogen,for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (80% ethyl acetate/hexanes eluent) to give 82 mg (55%) ofthe title compound as an amorphous foam. FDMS: m/e=389. α[D]₅₈₉ =+68.96(c=0.81, chloroform).

EXAMPLE 154

(+)-(4aR)-(10bR)-4-methyl-8-(2-[3-phenyl]tetrazoylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassiumcarbonate (158 mg, 1.14 mmol), 2-chloro-3-phenyltetrazole (83 mg, 0.46mmol) and 1 mL of anhydrous dimethylformamide, fitted with a refluxcondenser, and the stirred mixture was heated at 60°, under nitrogen,for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent) to give 81 mg (53%) of the titlecompound as a white solid. mp 128°-130°. FDMS: m/e=405. α[D]₅₈₉ =+69.47(c=0.57, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              65.16     65.35                                                H              5.72      5.85                                                 N              17.27     17.08                                                ______________________________________                                    

EXAMPLE 155

(+)-(4aR)-(10bR)-4-methyl-8-(2-[5-trifluoromethyl]pyridyl-thio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol),2-chloro-5-trifluoromethylpyridine (84 mg, 0.46 mmol) and 1.5 mL ofanhydrous dimethylformamide, fitted with a reflux condenser, and thestirred mixture was heated at 60°, under nitrogen, for 18 h. The mixturewas cooled, diluted with ethyl acetate (75 mL) and washed with brine(2×25 mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (ethyl acetateeluent) to give 90 mg (58%) of the title compound as an amorphous solid.mp 134°-140°. FDMS: m/e=406. α[D]₅₈₉ =+76.80 (c=0.42, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              62.05     61.89                                                H              5.21      5.31                                                 N              6.89      6.72                                                 ______________________________________                                    

EXAMPLE 156

(+)-(4aR)-(10bR)-4-methyl-8-(3-indazolylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol) ,1-(t-butoxy-carbonyl)-3-chloroindazole (116 mg, 0.46 mmol) and 1 mL ofanhydrous dimethylformamide, fitted with a reflux condenser, and thestirred mixture was heated at 60°, under nitrogen, for 18 h. The mixturewas cooled, diluted with ethyl acetate (75 mL) and washed with brine(2×25 mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (ethyl acetateeluent) to give 60 mg (16%) of the title compound as an oil. FDMS:m/e=377.

EXAMPLE 157

(+)-(4aR)-(10bR)-4-methyl-8-(2-[4-isopropyl]benzo-thiazolylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol),2-chloro-4-isopropylbenzothiazole (161 mg, 0.76 mmol) and 1 mL ofanhydrous dimethylformamide, fitted with a reflux condenser, and thestirred mixture was heated at 60°, under nitrogen, for 18 h. The mixturewas cooled, diluted with ethyl acetate (75 mL) and washed with brine(2×25 mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (ethyl acetateeluent) to give 57 mg (34%) of the title compound as an amorphous solid.mp 166°-170° FDMS: m/e=436.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              68.77     68.56                                                H              6.46      6.29                                                 N              6.42      6.36                                                 ______________________________________                                    

EXAMPLE 158

(+)-(4aR)-(10bR)-4-methyl-8-(6-chloro-2-benzohiazolylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol),2,6-dichloro-benzothiazole (155 mg, 0.76 mmol) and 1.5 mL of anhydrousdimethylformamide, fitted with a reflux condenser, and the stirredmixture was heated at 60°, under nitrogen, for 18 h. The mixture wascooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (ethyl acetateeluent) to give 86 mg (53%) of the title compound as an amorphous solid.mp 156°-162°. FDMS: m/e =429. α[D]₅₈₉ =+63.53 (c=0.66, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              61.60     60.89                                                H              4.93      5.35                                                 N              6.53      6.10                                                 ______________________________________                                    

EXAMPLE 159

(+)-(4aR)-(10bR)-4-methyl-8-(4-methyl-2-benzothiazolylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol),2-chloro-4-methylbenzothiazole (84 mg, 0.46 mmol) and 1 mL of anhydrousdimethylformamide, fitted with a reflux condenser, and the stirredmixture was heated at 60°, under nitrogen, for 18 h. The mixture wascooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (ethyl acetateeluent) to give 66 mg (43%) of the title compound as an amorphous solid.mp 134°-142° FDMS: m/e =408. α[D]₅₈₉ =+62.80 (c=0.74, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              67.61     67.41                                                H              5.92      6.11                                                 N              6.86      6.63                                                 ______________________________________                                    

EXAMPLE 160

(+)-(4aR)-(10bR)-4-methyl-8-(5-nitro-2-benzothiazolylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10boctahydrobezo[f]quinolin-3-one(100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol),2-chloro-5-nitro-benzothiazole (99 mg, 0.46 mmol) and 1 mL of anhydrousdimethylformamide, fitted with a reflux condenser, and the stirredmixture was heated at 60°, under nitrogen, for 18 h. The mixture wascooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (ethyl acetateeluent) to give 97 mg (58%) of the title compound as an amorphous solid.mp 96°-100°. FDMS: m/e=439. α[D]₅₈₉ =+61.35 (c=0.64, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              60.12     59.85                                                H              4.82      5.09                                                 N              9.56      9.35                                                 ______________________________________                                    

EXAMPLE 161

(+)-(4aR)-(10bR)-4-methyl-8-(6-methoxy-2-benzothiazolylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol),2-chloro-6-methoxy-benzothiazole (92 mg, 0.46 mmol) and 1.5 mL ofanhydrous dimethylformamide, fitted with a reflux condenser, and thestirred mixture was heated at 60°, under nitrogen, for 18 h. The mixturewas cooled, diluted with ethyl acetate (75 mL) and washed with brine(2×25 mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (ethyl acetateeluent) to give 76 mg (47%) of the title compound as an amorphous solid.mp 102°-107°. FDMS: m/e =424. α[D]₅₈₉ =+64.29 (c=0.71, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              65.07     64.81                                                H              5.70      5.98                                                 N              6.60      6.40                                                 ______________________________________                                    

EXAMPLE 162

(+)-(4aR)-(10bR)-4-methyl-8-(4-fluoro-2-benzothiazolylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol),2-chloro-4-fluorobenzothiazole (86 mg, 0.46 mmol and 1 mL of anhydrousdimethylformamide, fitted with a reflux condenser, and the stirredmixture was heated at 60°, under nitrogen, for 48 h. The mixture wascooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (80% ethylacetate/hexanes eluent) to give 91 mg (58%) of the title compound as anamorphous solid. mp 140°-145°. FDMS: m/e=412. α[D]₅₈₉ =+70.06 (c=0.52,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              64.05     64.29                                                H              5.13      5.21                                                 N              6.79      6.97                                                 ______________________________________                                    

EXAMPLE 163

(+)-(4aR)-(10bR)-4-methyl-8-(2-naphtho>1,2-d>-thiazolylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(100mg, 0.38 mmol), potassium carbonate (158 mg, 1.14mmol),2-chloronaphtho<1,2-d>thiazole (101 mg, 0.46 mmol) and 1.5 mL ofanhydrous dimethylformamide, fitted with a reflux condenser, and thestirred mixture was heated at 60°, under nitrogen, for 48 h. The mixturewas cooled, diluted with ethyl acetate (75 mL) and washed with brine(2×25 mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (80% ethylacetate/hexanes eluent) to give 94 mg (56%) of the title compound as anamorphous solid. mp 179°-184°. FDMS: m/e=444. α[D]₅₈₉ =+60.59 (c=0.67,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              70.24     69.95                                                H              5.44      5.50                                                 N              6.30      6.16                                                 ______________________________________                                    

EXAMPLE 164

(+)-(4aR)-(10bR)-4-methyl-8-(4-chloro-2-benzothiazolylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol),2,4-dichlorobenzo-thiazole (94 mg, 0.46 mmol) and 1 mL of anhydrousdimethyl formamide, fitted with a reflux condenser, and the stirredmixture was heated at 60°, under nitrogen, for 48 h. The mixture wascooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (80% ethylacetate/hexanes eluent) to give 80 mg (49%) of the title compound as anamorphous solid. mp 207°-209°. FDMS: m/e=429 α[D]₅₈₉ =+63.86 (c=0.57,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              61.60     61.80                                                H              4.93      5.13                                                 N              6.53      6.45                                                 ______________________________________                                    

EXAMPLE 165

(+)-(4aR)-(10bR)-4-methyl-8-(5,6-dichloro-2-benzothiazolyl-thio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol),2,5,6-trichloro benzothiazole (110 mg, 0.46 mmol) and 1 mL of anhydrousdimethylformamide, fitted with a reflux condenser, and the stirredmixture was heated at 60°, under nitrogen, for 18 h. The mixture wascooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (80% ethylacetate/hexanes eluent) to give 54 mg (31%) of the title compound as anamorphous foam. FDMS: m/e=463.

EXAMPLE 166

(+)-(4aR)-(10bR)-4-methyl-8-(5-nitro-2-pyridinylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo [f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol),2-bromo-5-nitropyridine (93 mg, 0.46 mmol) and 1.5 mL of anhydrousdimethylformamide, fitted with a reflux condenser, and the stirredmixture was heated at 60°, under nitrogen, for 18 h. The mixture wascooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (80% ethylacetate/hexanes eluent) to give 106 mg (73%) of the title compound as anamorphous foam. mp 188°-191°. FDMS: m/e=383. α[D]₅₈₉ =+57.07 (c=0.68,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              62.64     62.09                                                H              5.52      5.76                                                 N              10.96     10.40                                                ______________________________________                                    

EXAMPLE 167

(+)-(4aR)-(10bR)-4-methyl-8-(3-nitro-2-pyridinylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo [f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol),2-chloro-3-nitropyridine (73 mg, 0.46 mmol) and 1.5 mL of anhydrousdimethylformamide, fitted with a reflux condenser, and the stirredmixture was heated at 60°, under nitrogen, for 18 h. The mixture wascooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (90% ethylacetate/hexanes eluent) to give 95 mg (65%) of the title compound as anamorphous foam. mp 80°-84°. FDMS: m/e=383. α[D]₅₈₉ =+73.78 (c=0.49,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              62.64     62.94                                                H              5.52      5.68                                                 N              10.96     10.92                                                ______________________________________                                    

EXAMPLE 168

(+)-(4aR)-(10bR)-4-methyl-8-(6-nitro-2-quinolinylthio)-10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.38 mmol), potassium carbonate (96 mg, 1.14 mmol),2-chloro-6-nitroquinoline (96 mg, 0.46 mmol) and 1.5 mL of anhydrousdimethylformamide, fitted with a reflux condenser, and the stirredmixture was heated at 60°, under nitrogen, for 18h. The mixture wascooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (ethyl acetateeluent) to give 88 mg (53%) of the title compound as a tan solid. mp195°-196°. FDMS: m/e=433. α[D]₅₈₉ =+64.56 (c =0.78, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              66.49     66.25                                                H              5.35      5.51                                                 N              9.69      9.41                                                 ______________________________________                                    

EXAMPLE 169

(+)-(4aR)-(10bR)-4-methyl-8-(5-nitro-2-quinolinylthio)-10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(31 mg, 0.12 mmol), potassium carbonate (158 mg, 1.14 mmol),2-chloro-5-nitroquinoline (30 mg, 0.14 mmol) and 1 mL of anhydrousdimethylformamide, fitted with a reflux condenser, and the stirredmixture was heated at 60°, under nitrogen, for 18 h. The mixture wascooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (ethyl acetateeluent) to give 29 mg (56%) of the title compound as an amorphous foam.mp 149°-154°. FDMS: m/e=433. α[D]₅₈₉ =+60.00 (c=0.10, chloroform).

EXAMPLE 170

(+)-(4aR)-(10bR)-4-methyl-8-(8-nitro-2-quinolinylthio)-10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol),2-chloro-8-nitro- quinoline (96 mg, 0.46 mmol) and 1.5 mL of anhydrousdimethylformamide, fitted with a reflux condenser, and the stirredmixture was heated at 60°, under nitrogen, for 48 h. The mixture wascooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (80-100% ethylacetate/hexanes eluent) to give 90 mg (55%) of the title compound as asolid. mp 199°-200°. FDMS: m/e=433. α[D]₅₈₉ =+76.80 (c=0.42,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              66.49     66.28                                                H              5.35      5.52                                                 N              9.69      9.47                                                 ______________________________________                                    

EXAMPLE 171

(+)-(4aR)-(10bR)-4-methyl-8-(6-phenyl-3-pyridazinylthio)-10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol),3-chloro-6-phenyl-pyridazine (88 mg, 0.46 mmol) and 1.5 mL of anhydrousdimethylformamide, fitted with a reflux condenser, and the stirredmixture was heated at 60°, under nitrogen, for 48 h. The mixture wascooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (ethyl acetateeluent) to give 77 mg (49%) of the title compound as an amorphous solid.mp 199°-200°. FDMS: m/e=415. α[D]₅₈₉ =+67.26 (c=0.63, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              72.26     72.06                                                H              6.06      6.21                                                 N              10.11     9.93                                                 ______________________________________                                    

EXAMPLE 172

(+)-(4aR)-(10bR)-4-methyl-8-(2-phenyl-4-quinazolinylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo If]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14mmol),4-chloro-2-phenyl-quinazoline (111 mg, 0.46 mmol) and 1 mL of anhydrousdimethylformamide, fitted with a reflux condenser, and the stirredmixture was heated at 60°, under nitrogen, for 18 h. The mixture wascooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (80-100% ethylacetate/hexanes eluent gradient) to give 112 mg (63%) of the titlecompound as an off white solid. mp 185°193°. FDMS: m/e=465. α[D]₅₈₉=+49.59 (c=0.57, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              74.81     73.56                                                H              5.84      5.94                                                 N              9.02      8.95                                                 ______________________________________                                    

EXAMPLE 173

(+)-(4aR)-(10bR)-4-methyl-8-(6-fluoro-2-quinolinylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol),2-chloro-6-fluoro-quinoline (84 mg, 0.46 mmol) and 1.5 mL of anhydrousdimethylformamide, fitted with a reflux condenser, and the stirredmixture was heated at 60°, under nitrogen, for 48 h. The mixture wascooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (80% ethylacetate/hexanes eluent) to give 96 mg (62%) of the title compound as asolid. mp 152°-155°. FDMS: m/e=406. α[D]₅₈₉ =+63.16 (c=0.61,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              70.91     70.76                                                H              5.70      5.83                                                 N              6.89      6.81                                                 ______________________________________                                    

EXAMPLE 174

(+)-(4aR)-(10bR)-4-methyl-8-(8-fluoro-2-quinolinylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol),2-chloro-8-fluoroquinoline (84 mg, 0.46 mmol) and 1.5 mL of anhydrousdimethylformamide, fitted with a reflux condenser, and the stirredmixture was heated at 60°, under nitrogen, for 18 h. The mixture wascooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (80% ethylacetate/hexanes eluent) to give 78 mg (50%) of the title compound as anamorphous foam. FDMS: m/e=406. α[D]₅₈₉ =+63.29 (c=0.56, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              70.91     71.15                                                H              5.70      5.82                                                 N              6.89      6.94                                                 ______________________________________                                    

EXAMPLE 175

(+)-(4aR)-(10bR)-4-methyl-8-(4-thieno[3,2-c]pyridylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol),4-chlorothieno[3,2-c]pyridine (78 mg, 0.46 mmol) and 1 mL of anhydrousdimethyl formamide, fitted with a reflux condenser, and the stirredmixture was heated at 60°, under nitrogen, for 18 h. The mixture wascooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (80% ethylacetate/hexanes eluent) to give 37 mg (25%) of the title compound as awhite solid. mp 196°-197°. FDMS: m/e=394. α[D]₅₈₉ =+75.17 (c=0.57,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              66.97     66.70                                                H              5.62      5.70                                                 N              7.10      6.88                                                 ______________________________________                                    

EXAMPLE 176

(+)-(4aR)-(10bR)-4-methyl-8-(10-oxo-10H-2-pyridazino[6,1-b]-quinazolinylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol),2-chloro-10H-pyridazino[6,1b]quinazolin-10-one (107 mg, 0.46 mmol) and 1mL of anhydrous dimethylformamide, fitted with a reflux condenser, andthe stirred mixture was heated at 60°, under nitrogen, for 18 h. Themixture was cooled, diluted with ethyl acetate (75 mL) and washed withbrine (2×25 mL). The combined organic extracts were dried over sodiumsulfate, concentrated, and purified by silica gel chromatography (0-10%methanol/ethyl acetate eluent gradient) to give 103 mg (62%) of thetitle compound as an amorphous foam. mp 110°-114°. FDMS: m/e=456.α[D]₅₈₉ =+54.77 (c=0.49, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              68.40     68.22                                                H              5.30      5.31                                                 N              12.27     12.01                                                ______________________________________                                    

EXAMPLE 177

(+)-(4aR)-(10bR)-4-methyl-8-(3-phenyl-1-isoquinolinylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(86 mg, 0.33 mmol), potassium carbonate (158 mg, 1.14 mmol),1-chloro-3-phenyl- isoquinoline (95 mg, 0.40 mmol) and 1 mL of anhydrousdimethylformamide, fitted with a reflux condenser, and the stirredmixture was heated at 60°, under nitrogen, for 18 h. The mixture wascooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (80% ethylacetate/hexanes eluent) to give 64 mg (42%) of the title compound as anoff white solid. mp 183°-189°. FDMS: m/e=464. α[D]₅₈₉ =+54.61 (c=0.53,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              77.55     77.26                                                H              6.07      6.16                                                 N              6.03      6.16                                                 ______________________________________                                    

EXAMPLE 178

(+)-(4aR)-(10bR)-4-methyl-8-(3-methyl-2-quinolinylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(37 mg, 0.14 mmol), potassium carbonate (158 mg, 1.14 mmol),2-chloro-3-methyl-quinoline (30 mg, 0.17 mmol) and 1 mL of anhydrousdimethylformamide, fitted with a reflux condenser, and the stirredmixture was heated at 60°, under nitrogen, for 18 h. The mixture wascooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (80 ethylacetate/hexanes eluent) to give 9 mg (16%) of the title compound as anamorphous foam. mp 185°-193°. FDMS: m/e=402.

EXAMPLE 179

(+)-(4aR)-(10bR)-4-methyl-8-[3-phenyl-4-(4-methoxyphenyl)-2-quinolinylthio]-10b-methyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (60 mg, 0.23 mmol), potassiumcarbonate (158 mg, 1.14 mmol),2-chloro-3-phenyl-4-(4-methoxyphenyl)quinoline (95 mg, 0.27 mmol) and 1mL of anhydrous dimethylformamide, fitted with a reflux condenser, andthe stirred mixture was heated at 60°, under nitrogen, for 18h. Themixture was cooled, diluted with ethyl acetate (75 mL) and washed withbrine (2×25 mL). The combined organic extracts were dried over sodiumsulfate, concentrated, and purified by silica gel chromatography (ethylacetate eluent) to give 56 mg (43%) of the title compound as an offwhite solid. mp 239°-242°. FDMS: m/e=570. α[D]₅₈₉ =+45.00 (c=1.40,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              77.86     77.58                                                H              6.00      6.12                                                 N              4.91      4.94                                                 ______________________________________                                    

EXAMPLE 180

(+)-(4aR)-(10bR)-4-methyl-8-(3-[1,2-benzisothiazolyl]thio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol),3-chloro-1,2-benzisothiazole (78 mg, 0.46 mmol) and 1 mL of anhydrousdimethylformamide, fitted with a reflux condenser, and the stirredmixture was heated at 60°, under nitrogen, for 18 h. The mixture wascooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (80-100% ethylacetate/hexanes eluent gradient) to give 54 mg (36%) of the titlecompound as an amorphous foam. FDMS: m/e=394.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              66.97     67.05                                                H              5.62      5.83                                                 N              7.10      7.03                                                 ______________________________________                                    

EXAMPLE 181

(+)-(4aR)-(10bR)-4-methyl-8-(2-[4,6-diphenyl]pyridylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzof]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(78 mg, 0.30 mmol), potassium carbonate (158 mg, 1.14 mmol),2-chloro-4,6-diphenylpyridine (95 mg, 0.36 mmol) and 1.5 mL of anhydrousdimethylformamide, fitted with a reflux condenser, and the stirredmixture was heated at 60°, under nitrogen, for 18 h. The mixture wascooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (80% ethylacetate/hexanes eluent) to give 40 mg (27%) of the title compound as anamorphous solid. FDMS: m/e=490. α[D]₅₈₉ =+37.97 (c=0.39, chloroform).

EXAMPLE 182

(+)-(4aR)-(10bR)-4-methyl-8-(4-methoxy-2-benzothiazolylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol),2-chloro-4-methoxybenzothiazole (92 mg, 0.46 mmol) and 1.5 mL ofanhydrous dimethylformamide, fitted with a reflux condenser, and thestirred mixture was heated at 60°, under nitrogen, for 18 h. The mixturewas cooled, diluted with ethyl acetate (75 mL) and washed with brine(4×25 mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (ethyl acetateeluent) to give 107 mg (66%) of the title compound as an off whitesolid. mp 200°-205°. FDMS: m/e=424. α[D]₅₈₉ =+60.56 (c=0.96,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              65.07     64.43                                                H              5.70      5.55                                                 N              6.60      7.81                                                 ______________________________________                                    

EXAMPLE 183

(+)-(4aR)-(10bR)-4-methyl-8-(4-bromo-2-benzothiazolylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol),2-chloro-4-bromobenzothiazole (114 mg, 0.46 mmol) and 1 mL of anhydrousdimethylformamide, fitted with a reflux condenser, and the stirredmixture was heated at 60°, under nitrogen, for 18 h. The mixture wascooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (ethyl acetateeluent) to give 142 mg (79%) of the title compound as an off whitesolid. mp 206°-210°. FDMS: m/e=474. α[D]₅₈₉ =+56.25 (c=0.59,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              55.81     55.63                                                H              4.47      4.62                                                 N              5.92      6.16                                                 ______________________________________                                    

EXAMPLE 184

(+)-(4aR)-(10bR)-4-methyl-8-(4-phenyl-2-benzothiazolylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol),2-chloro-4-phenyl-benzothiazole (113 mg, 0.46 mmol) and 1 mL ofanhydrous dimethylformamide, fitted with a reflux condenser, and thestirred mixture was heated at 60°, under nitrogen, for 18 h. The mixturewas cooled, diluted with ethyl acetate (75 mL) and washed with brine(4×25 mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (ethyl acetateeluent) to give 110 mg (61%) of the title compound as an amorphous foam.FDMS: m/e=470. α[D]₅₈₉ =+53.51 (c=0.66, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              71.46     71.22                                                H              5.57      5.69                                                 N              5.95      5.82                                                 ______________________________________                                    

EXAMPLE 185

(+)-(4aR)-(10bR)-4-methyl-8-(4,7-dimethyl-2-benzothiazolylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(100mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol),2-chloro-4,7-dimethylbenzothiazole (91 mg, 0.46 mmol) and 1 mL ofanhydrous dimethylformamide, fitted with a reflux condenser, and thestirred mixture was heated at 60°, under nitrogen, for 18 h. The mixturewas cooled, diluted with ethyl acetate (75 mL) and washed with brine(2×25 mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (80% ethylacetate/hexanes eluent) to give 111 mg (69%) of the title compound as anamorphous foam. FDMS: m/e=422. α[D]₅₈₉ =+63.27 (c=0.95, chloroform).

EXAMPLE 186

(+)-(4aR)-(10bR)-4-methyl-8-(4-propyl-2-benzothiazolylthio)-t0b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38mmol), potassium carbonate (158 mg, 1.14 mmol),2-chloro-4-propyl-benzothiazole (97 mg, 0.46 mmol) and 1 mL of anhydrousdimethylformamide, fitted with a reflux condenser, and the stirredmixture was heated at 60°, under nitrogen, for 18 h. The mixture wascooled, diluted with ethyl acetate (75 mL) and washed with brine (6×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (80% ethylacetate/hexanes eluent) to give 116 mg (70%) of the time compound as anamorphous solid. mp 109°-111°. FDMS: m/e=436. α[D]₅₈₉ =+45.00 (c=0.80,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              68.77     68.50                                                H              6.46      6.57                                                 N              6.42      6.44                                                 ______________________________________                                    

EXAMPLE 187

(+)-(4aR)-(10bR)-4-methyl-8-(4-ethyl-2-benzothiazolylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 200 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(1.36 g, 5.20 mmol), potassium carbonate (2.16 g, 15.6 mmol),2-chloro-4-ethyl-benzothiazole (1.23 g, 6.20 mmol) and 14 mL ofanhydrous dimethylformamide, fitted with a reflux condenser, and thestirred mixture was heated at 60°, under nitrogen, for 18h. The mixturewas cooled, diluted with ethyl acetate (750 mL) and washed with brine(6×250 mL). The combined organic extracts were dried over sodiumsulfate, concentrated, and purified by silica gel chromatography (80%ethyl acetate/hexanes eluent) to give 1.51g (69%) of the title compoundas an amorphous foam. FDMS: m/e=422. α[D]₅₈₉ =+62.74 (c=0.67,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              68.21     68.40                                                H              6.20      6.22                                                 N              6.63      6.49                                                 ______________________________________                                    

EXAMPLE 188

(+)-(4aR)-(10bR)-4-methyl-8-(4-trifluoromethoxy-2-benzo-thiazolylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol),2-chloro-4-trifluoromethoxybenzothiazole (117 mg, 0.46 mmol) and 1.5 mLof anhydrous dimethylformamide, fitted with a reflux condenser, and thestirred mixture was heated at 60°, under nitrogen, for 18 h. The mixturewas cooled, diluted with ethyl acetate (75 mL) and washed with brine(4×25 mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (ethyl acetateeluent) to give 141 mg (77%) of the title compound as a white solid. mp168°-173°. FDMS: m/e=478. α[D]₅₈₉ =+57.89 (c=0.59, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              57.73     57.50                                                H              4.42      4.52                                                 N              5.85      5.78                                                 ______________________________________                                    

EXAMPLE 189

(+)-(4aR)-(t0bR)-4-methyl-8-[4,7-di(t-butyl)-2-benzothiazolylthio]-10b-methyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]-quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto -10b-methyl -1,2,3,4,4 a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassiumcarbonate (158 mg, 1.14 mmol) 2-chloro-4 7-di(t-butyl) benzothiazole(130 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fittedwith a reflux condenser, and the stirred mixture was heated at 60°,under nitrogen, for 18 h. The mixture was cooled, diluted with ethylacetate (75 mL) and washed with brine (4×25 mL). The combined organicextracts were dried over sodium sulfate, concentrated, and purified bysilica gel chromatography (80% ethyl acetate/hexanes eluent) to give 33mg (17%) of the title compound as an amorphous foam. FDMS: m/e=506.

EXAMPLE 190

(+)-{4aR)-(10bR)-4-methyl-8-(4-methyl-7-trifluoromethyl-2-benzothiazolylthio)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol),2-chloro-4-methyl-7-trifluoromethylbenzothiazole (116 mg, 0.46 mmol) and1.5 mL of anhydrous dimethyl formamide, fitted with a reflux condenser,and the stirred mixture was heated at 60°, under nitrogen, for 18 h. Themixture was cooled, diluted with ethyl acetate (75 mL) and washed withbrine (4×25 mL). The combined organic extracts were dried over sodiumsulfate, concentrated, and purified by silica gel chromatography (80%ethyl acetate/hexanes eluent) to give 94 mg (52%) of the title compoundas an amorphous foam. mp 50°-54°. FDMS: m/e=476.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              60.49     60.79                                                H              4.86      5.14                                                 N              5.88      5.75                                                 ______________________________________                                    

EXAMPLE 191

(+)-(4aR)-{10bR)-8-(3-isoquinolinylmethylthio)-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline-3-one

To a stirred solution of(4aR)-(10bR)-8-thio-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline-3-one(100 mg, 0.38 mmol) in dimethylformamide (2 mL) was added powderedpotassium carbonate (158 mg, 1.14 mmol) followed by3-bromomethylisoquinoline (89 mg, 0.4 mmol). The mixture was purged withnitrogen and heated to 60° for 14 h. The mixture was cooled to ambienttemperature and partitioned between water and ethyl acetate. The aqueousphase was back extracted with ethyl acetate and the combined organicphases were washed with saturated brine and dried over anhydrous sodiumsulfate. Removal of solvent afforded crude product. Purification byflash chromatography on silica gel (0.5% aq ammonium hydroxide/ethylacetate) followed by crystallization from ethyl acetate afforded productas a crystalline solid (91 mg), mp=129°-130°. m/e 402. OR (c=1.0,methanol) @ 589 mM, +64.2°, @ 365 nM, +226.7°.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              74.59     74.87                                                H              6.51      6.45                                                 N              6.96      7.09                                                 ______________________________________                                    

EXAMPLE 192

(+)-(4aR)-(10bR)-8-(2-benzothiazolylmethylthio)-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo [f]quinoline-3-one

To a stirred solution of(4aR)-(10bR)-8-thio-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline-3-one(100 mg, 0.38 mmol}in dimethylformamide (2 mL) was added powderedpotassium carbonate (158 mg, 1.14 mmol) followed by2-chloromethylbenzothiazole (73 mg, 0.4 mmol). The mixture was purgedwith nitrogen and heated to 60° for 14 h. The mixture was cooled toambient temperature and partitioned between water and ethyl acetate. Theaqueous phase was back extracted with ethyl acetate and the combinedorganic phases were washed with saturated brine and dried over anhydroussodium sulfate. Removal of solvent afforded crude product. Purificationby flash chromatography on silica gel (0.5% aq ammonium hydroxide/ethylacetate) followed by crystallization from diethyl ether/ethyl acetateafforded product as a crystalline solid (55 mg), mp=78°-80°. m/e 408. OR(c=0.3, methanol) @ 589 nM, +66.3°.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              67.61     67.51                                                H              5.92      6.05                                                 N              6.86      6.63                                                 ______________________________________                                    

EXAMPLE 193

(4aR)-(10bR)-4,10b-dimethyl-8-(7-chloro-2-benzothiazolylthio)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline-3-one

A 303 mg portion of 2,7-dichlorobenzothiazole and 316 mg of potassiumcarbonate were dissolved in 3 ml of anhydrous dimethylformamide. To thesolution was added 400 mg of(4aR)-10bR)-8-thio-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline-3-onedissolved in 6 ml of anhydrous dimethylformamide, and the mixture waswarmed to 60° and stirred over night. The mixture was then diluted with60 ml of ethyl acetate and washed 4 times with brine. The organic layerwas dried over sodium sulfate, filtered and evaporated to obtain 638 mgof impure product, which was evaporated under high vacuum and purifiedby rotary chromatography on silica gel, eluting with ethyl acetate, toobtain 195 mg of the desired product. mp 90°-91°. FDMS: m/e=+428.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              61.60     61.83                                                H              4.93      5.09                                                 N              6.53      6.49                                                 ______________________________________                                    

EXAMPLE 194.

(4aR)-(10bR)-4,10b-dimethyl-8-(5-chloro-2-benzothiazolylthio)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline-3-one

400 mg of (4aR)-(10bR)-8-thio-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinoline-3-one was reacted with2,5-dichlorobenzothiazole as described in Example 193 to obtain 56 mg ofthe desired product. mp 179°-180°. FDMS: m/e=+428.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              61.60     61.30                                                H              4.93      4.89                                                 N              6.53      6.51                                                 ______________________________________                                    

EXAMPLE 195

(4aR)-(10bR)-8-diphenylmethylthio-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinoline-3-one

500 mg of(4aR)-(10bR)-8-thio-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinoline-3-onewas dissolved in 12.5 ml of dimethylformamide, and to the solution wasadded 789 mg of potassium carbonate, followed by 405 μl of diphenylchloromethane. The mixture was stirred at 60° for 18 hours, cooled andpartitioned between ethyl acetate and water. The organic layer waswashed 3 times with brine, dried over sodium sulfate and concentratedunder vacuum to obtain 896 mg of crude product. That material waspurified on a Chromatotron, eluting with ethyl acetate, and theproduct-containing fractions were recrystallized from ethylacetate/hexane to obtain 146 mg of the desired product. mp 102°-104°FDMS: m/e=+427. α[D]₅₈₉ =60.28.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              78.65     78.65                                                H              6.84      6.72                                                 N              3.28      3.47                                                 ______________________________________                                    

The following preparation and examples illustrate the synthesis ofcompounds of the present invention through an intermediate having aboronic acid substituent on the benzoquinolinone nucleus.

Preparation 9

(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid

To a solution of(+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one(5.0 g, 16.2 mmol) in 500 mL of anhydrous THF was added t-butyllithium(37.5 mL, 1.3M solution in cyclohexane) at -78°. The mixture was allowedto stir at -78° for 75 min, and a solution of triisopropyl borate (2.0equiv.) in 12.5 mL of anhydrous THF was added dropwise. The mixture wasstirred for an additional 45 min, then the cold bath was removed, andthe mixture was allowed to warm to room temperature. The mixture wasquenched with 5N hydrochloric acid (50 mL), and volatiles were removedon rotary evaporator. The mixture was then treated with 35 mL of 5Nsodium hydroxide, and was extracted with THF (300 mL). The organicextract was dried over sodium sulfate, filtered, and concentrated. Theresulting solid was heated in boiling ethyl acetate for 15 min, followedby filtration (while still hot), to yield 3.65 g (82%) of the titlecompound as a white solid. mp 200° (decomp.) α[D]₅₈₉ =+72.27 (c=0.89,methanol).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              65.96     65.74                                                H              7.38      7.73                                                 N              5.13      4.94                                                 ______________________________________                                    

EXAMPLE 196

(+)-(4aR)-(10bR)-8-(3-quinolinyl)-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin3-one-8-boronic acid (168 mg, 0.65mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol) ,3-bromoquinoline (135 mg, 0.65 mmol), 0.65 mL of aqueous 2M sodiumcarbonate and 2 mL of THF, fitted with a reflux condenser, and thestirred mixture was heated at 80°, under nitrogen, for 24 h. The mixturewas cooled, diluted with chloroform (75 mL) and washed with brine (2×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (5%methanol/ethyl acetate eluent) to give 141 mg (63%) of the titlecompound as a white solid. mp 265°-266°. FDMS: m/e=342. α[D]₅₈₉ =+88.70(c=0.84, chloroform).

EXAMPLE 197

(+)-(4aR)-(10bR)-8-(4-[2,8-bistrifluoromethyl]quinolinyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f]quinolin3-one-8-boronic acid (168 mg, 0.65 mmol),tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol),4-bromo-2,8-bis(trifluoromethyl)quinoline (224 mg, 0.65 mmol), 0.65 mLof 2M sodium carbonate and 2 mL of THF, fitted with a reflux condenser,and the stirred mixture was heated at 80°, under nitrogen, for 24 h. Themixture was cooled, diluted with chloroform (75 mL) and washed withbrine (2×25 mL). The combined organic extracts were dried over sodiumsulfate, concentrated, and purified by silica gel chromatography (ethylacetate eluent) to give 186 mg (60%) of the title compound as a whitesolid. mp 214°-215°. FDMS: m/e=478. α[D]₅₈₉ =+62.00 (c=1.10,chloroform).

EXAMPLE 198.

(+)-(4aR)-(10bR)-8-(2-thiazolyl)-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin3-one-8-boronicacid (168 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (23mg, 0.02 mmol), 2-bromothiazole (107 mg, 0.65 mmol), 0.65 mL of 2Msodium carbonate and 2mL of THF, fitted with a reflux condenser, and thestirred mixture was heated at 80°, under nitrogen, for 24 h. The mixturewas cooled, diluted with chloroform (75 mL) and washed with brine (2×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (5%methanol/ethyl acetate eluent) to give 64 mg (35%) of the title compoundas a white solid. mp 206°-207°. FDMS: m/e=298. α[D]₅₈₉ =+101.7 (c=0.97,chloroform).

EXAMPLE 199

(+)-(4aR)-(10bR)-8-(5-nitro-2-pyridinyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin3-one-8-boronic acid (168 mg, 0.65mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol),2-bromo-5nitropyridine (132 mg, 0.65 mmol), 0.65 mL of 2M sodiumcarbonate and 2mL of THF, fitted with a reflux condenser, and thestirred mixture was heated at 80°, under nitrogen, for 24 h. The mixturewas cooled, diluted with chloroform (75 mL) and washed with brine (2×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (ethyl acetateeluent) to give 71 mg of the title compound as a white solid. mp123°-124°. FDMS: m/e=337. α[D]₅₈₉ =+85.60 (c=0.61, chloroform).

EXAMPLE 200

(+)-(4aR)-(10bR)-4-methyl-8-(4-isoquinolinyl)-10b-methyl-1, 2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-10bR)-4-methyl-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium (0) (23mg, 0.02 mmol), 4bromoisoquinoline (135 mg, 0.65 mmol), 0.65 mL ofsodium carbonate and 2 mL of THF, fitted with a reflux condenser, andthe stirred mixture was heated at 80°, under nitrogen, for 24 h. Anadditional 23 mg of the palladium reagent was added, and the mixture washeated an additional 24 h. The mixture was cooled, diluted withchloroform (75 mL) and washed with brine (2×25 mL). The combined organicextracts were dried over sodium sulfate, concentrated, and purified bysilica gel chromatography ethyl acetate eluent) to give 110 mg (47%) ofthe title compound as an amorphous foam. FDMS: m/e=356. α[D]₅₈₉ =+67.82(c=0.40, methanol).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              80.87     80.57                                                H              6.79      6.82                                                 N              7.86      7.69                                                 ______________________________________                                    

EXAMPLE 201

(+)-(4aR)-(10bR)-4-methyl-8-(3-quinolinyl )-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-{4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23mg, 0.02 mmol), 3-bromoquinoline (135 mg, 0.65 mmol), 0.65 mL of 2Msodium carbonate solution and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24 h. An additional 23 mg of the palladium reagent was added, andthe mixture was heated an additional 24 h. The mixture was cooled,diluted with chloroform (75 mL) and washed with brine (2×25 mL). Thecombined organic extracts were dried over sodium sulfate, concentrated,and purified by silica gel chromatography (ethyl acetate eluent) to give130 mg (56%) of the title compound as an amorphous solid. mp 180°-185°.FDMS: m/e=356. α[D]₅₈₉ =+80.22 (c=0.37, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              80.87     80.65                                                H              6.79      6.52                                                 N              7.86      7.68                                                 ______________________________________                                    

EXAMPLE 202

(+)-(4aR)-(10bR)-4-methyl-8-(5-nitro-2-pyridinyl )-10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo [f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (1 78 mg, 0.65 mmol), tetrakis (triphenylphosphine ) palladium (0 )(2 3 mg, 0.02 mmol), 2-bromo-5-nitropyridine (132 mg, 0.65 mmol), 0.65mL of 2M aqueous sodium carbonate and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24 h.

The mixture was cooled, diluted with ethyl acetate (75 mL) and washedwith brine (2×25 mL). The combined organic extracts were dried oversodium sulfate, concentrated, and purified by silica gel chromatography(ethyl acetate eluent) to give 148 mg (65%) of the title compound as anamorphous foam. mp 70°-80°. FDMS: m/e=351. α[D]₅₈₉ =+85.59 (c=0.48,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              68.26     67.81                                                H              6.02      6.18                                                 N              11.96     11.42                                                ______________________________________                                    

EXAMPLE 203

(+)-(4aR)-(!0bR)-4-methyl-8-[2,8-bis(trifluoromethyl)-4-quinolinyl]-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a-,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (23mg, 0.02 mmol), 2,8-bis(trifluoromethyl)-4-bromoquinoline (224 mg, 0.65mmol), 0.65 mL of 2M aqueous sodium carbonate and 2 mL of THF, fittedwith a reflux condenser, and the stirred mixture was heated at 80°,under nitrogen, for 24 h. The mixture was cooled, diluted with ethylacetate (75 mL) and washed with brine (2×25 mL). The combined organicextracts were dried over sodium sulfate, concentrated, and purified bysilica gel chromatography (ethyl acetate eluent) to give 153 mg (48%) ofthe title compound as an amorphous foam. mp 100°-106°. FDMS: m/e=492.α[D]₅₈₉ =+51.86 (c=0.47, chloroform)

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              63.41     63.25                                                H              4.50      4.77                                                 N              5.69      5.40                                                 ______________________________________                                    

EXAMPLE 204

(+)-(4aR)-(10bR)-4-methyl-8-(4-methylsulfonylphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinol in-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronic acid (178 mg, 0.65mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol),methyl 4bromophenylsulfone (153 mg, 0.65 mmol), 0.65 mL of 2M aqueoussodium carbonate and 2 mL of THF, fitted with a reflux condenser, andthe stirred mixture was heated at 80°, under nitrogen, for 24 h. Themixture was cooled, diluted with ethyl acetate (75 mL) and washed withbrine (2×25 mL). The combined organic extracts were dried over sodiumsulfate, concentrated, and purified by silica gel chromatography (ethylacetate eluent) no give 137 mg (55%) of the title compound as a whitesolid. mp 229°. FDMS: m/e=383. α[D]₅₈₉ =+28.24 (c=0.23, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              68.90     69.10                                                H              6.57      6.65                                                 N              3.65      3.89                                                 ______________________________________                                    

EXAMPLE 205

(+)-(4aR)-(10bR)-4-methyl-8-(2,3,4,5,6-pentafluorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23mg, 0.02 mmol), 1-bromo-2,3,4,5,6-pentafluorobenzene (161 mg, 0.65mmol), 0.65 mL of 2M aqueous sodium carbonate and 2 mL of THF, fittedwith a reflux condenser, and the stirred mixture was heated at 80°,under nitrogen, for 24 h. The mixture was cooled, diluted withchloroform (75 mL) and washed with brine (2×25 mL). The combined organicextracts were dried over sodium sulfate, concentrated, and purified bysilica gel chromatography (ethyl acetate eluent) to give 97 mg (38%) ofthe title compound as an amorphous foam. mp 92°-100°. FDMS: m/e=395.α[D]₅₈₉ =+64.15 (c=0.42, chloroform).

EXAMPLE 206

(+)-(4aR)-(10bR)-4-methyl-8-(3,4,5-trifluorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo [f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (1 78 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium (0)(23 mg, 0.02 mmol), 1-bromo-3,4,5-trifluorobenzene (137 mg, 0.6 5 mmol),0.65 mL of 2M aqueous sodium carbonate and 2 mL of THF, fitted with areflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 24 h. The mixture was cooled, diluted with ethyl acetate(75 mL) and washed with brine (2×25 mL). The combined organic extractswere dried over sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent) to give 117 mg (50%) of the titlecompound as an amorphous wax. FDMS: m/e=359 α[D]₅₈₉ =+75.86 (c=0.47,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              70.18     70.41                                                H              5.61      5.81                                                 N              3.90      3.78                                                 ______________________________________                                    

EXAMPLE 207

(+)-(4aR)-(10bR)-4-methyl-8-(1-oxo-5-indanyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo [f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23mg, 0.02 mmol), 5-bromo-1-indanone (137 mg, 0.65 mmol), 0.65 mg of 2Maqueous sodium carbonate and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24 h. The mixture was cooled, diluted with ethyl acetate (75 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent) to give 91 mg (39%) of the titlecompound as a white solid. mp 175°-178°. FDMS: m/e=359. α[D]₅₈₉ =+74.81(c=0.53, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              80.19     79.08                                                H              7.01      7.01                                                 N              3.90      4.08                                                 ______________________________________                                    

EXAMPLE 208

(+)-(4aR)-(10bR)-4-methyl-8-(2-fluoro-3-trifluoromethylphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo [f]-quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (23mg, 0.02 mmol), 1-bromo-2-fluoro-3-trifluoromethylbenzene (158 mg, 0.65mmol), 0.65 mL of 2M aqueous sodium carbonate and 2 mL of THF, fittedwith a reflux condenser, and the stirred mixture was heated at 80°,under nitrogen, for 24 h. The mixture was cooled, diluted with ethylacetate (75 mL) and washed with brine (2×25 mL). The combined organicextracts were dried over sodium sulfate, concentrated, and purified bysilica gel chromatography (ethyl acetate eluent) to give 130 mg (51%) ofthe title compound as an oil. FDMS: m/e=391. α[D]₅₈₉ =+68.49 (c=0.38,chloroform).

EXAMPLE 209

(+)-(4aR)-(10bR)-4-methyl-8-(3-[1-benzyl-4-piperidinyl-carboxamido]phenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23mg, 0.02 mmol), 1-bromo-3-(1-benzyl-4-piperidinylcarboxamido)benzene(243 mg, 0.65 mmol), 0.65 mL of 2M aqueous sodium carbonate and 2 mL ofTHF, fitted with a reflux condenser, and the stirred mixture was heatedat 80°, under nitrogen, for 24 h. The mixture was cooled, diluted withethyl acetate (75 mL) and washed with brine (2×25 mL). The combinedorganic extracts were dried over sodium sulfate, concentrated, andpurified by silica gel chromatography (5% methanol/ethyl acetate eluent)to give 148 mg (44%) of the title compound as an amorphous foam. FDMS:m/e=521. α[D]₅₈₉ =53.50 (c=0.45 , chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              78.28     77.50                                                H              7.53      7.60                                                 N              8.05      7.65                                                 ______________________________________                                    

EXAMPLE 210

(+)-(4aR)-(10bR)-4-methyl-8-(2-fluoro-4-trifluoromethyl-phenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), 4-bromo-3-fluorobenzotrifluoride (158 mg, 0.78mmol), 0.65 mL of sodium carbonate and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 48 h.

The mixture was cooled, diluted with chloroform (75 mL) and washed withbrine (2×25 mL). The combined organic extracts were dried over sodiumsulfate, concentrated, and purified by silica gel chromatography (ethylacetate eluent) to give 171 mg (67%) of the title compound as anamorphous solid. mp 72°-79°. FDMS: m/e=391. α[D]₅₈₉ =+62.50 (c=0.48,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              67.51     67.72                                                H              5.41      5.65                                                 N              3.58      3.33                                                 ______________________________________                                    

EXAMPLE 211

(+)-(4aR)-(10bR)-4-methyl-8-(2-fluoro-5-trifluoromethylphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23mg, 0.02 mmol), 3-bromo-4-fluorobenzotrifluoride (158 mg, 0.65 mmol),0.65 mL of 2M aqueous sodium carbonate and 2 mL of THF, fitted with areflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 24 h. The mixture was cooled, diluted with ethyl acetate(75 mL) and washed with brine (2×25 mL). The combined organic extractswere dried over sodium sulfate, concentrated, and purified by silica gelchromatography (70% ethyl acetate/hexanes eluent) to give 113 mg (44%)of the title compound as an oil. FDMS: m/e=391. α[D]₅₈₉ =+55.84 (c=0.34,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              67.51     67.73                                                H              5.41      5.62                                                 N              3.58      3.31                                                 ______________________________________                                    

EXAMPLE 212(+)-(4aR)-(10bR)-4-methyl-8-(3-methylthiophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis triphenylphosphine) palladium (0) (23mg, 0.02 mmol), 3-methylthio-1-bromobenzene (132 mg, 0.65 mmol), 0.65 mLof 2M aqueous sodium carbonate and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 48 h. The mixture was cooled, diluted with chloroform (75 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent) to give 110 mg (48%) of the titlecompound as an oily solid. FDMS: m/e=351. α[D]₅₈₉ =+90.00 (c=0.17,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              75.17     75.02                                                H              7.17      7.13                                                 N              3.98      3.77                                                 ______________________________________                                    

EXAMPLE 213(+)-(4aR)-(10bR)-4-methyl-8-(4-carboxamidophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23mg, 0.02 mmol), 4-carboxamido-1-bromobenzene (130 mg, 0.65 mmol), 0.65mL of 2M sodium carbonate and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24 h. The mixture was cooled, diluted with ethyl acetate (75 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (0-10% methanol/ethyl acetate eluent gradient) to give 21mg (9%) of the title compound as amorphous foam. mp 177°-189° (decomp.)FDMS: m/e=348.

EXAMPLE 214

(+)-(4aR)-(10bR)-4-methyl-8-[2-oxo-3-(N,N-diethylcarboxamido)-1-2H-benzopyran-6-yl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium(0) (23mg, 0.02 mmol), 6-bromo-2-oxo-3-(N,N-diethylcarboxamido)-1-2H-benzopyran(211 mg, 0.65 mmol), 0.65 mL of 2M sodium carbonate and 2 mL of THF,fitted with a reflux condenser, and the stirred mixture was heated at80°, under nitrogen, for 24 h. The mixture was cooled, diluted withethyl acetate (75 mL) and washed with brine (2×25 mL). The combinedorganic extracts were dried over sodium sulfate, concentrated, andpurified by silica gel chromatography (5% methanol/ethyl acetate eluent)to give 138 mg (45%) of the title compound as an amorphous foam. mp120°-125°. FDMS: m/e=472. α[D]₅₈₉ =+54.69(c=0.49, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              73.71     73.49                                                H              6.82      6.85                                                 N              5.93      5.86                                                 ______________________________________                                    

EXAMPLE 215(+)-(4aR)-(10bR)-4-methyl-8-[2-(t-butylcarbonylamino)-5-pyridinyl]-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid 178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23mg, 0.02 mmol), 5-bromo-2-(t-butylcarbonylamino)pyridine 167 mg, 0.65mmol), 0.65 mL of 2M aqueous sodium carbonate and mL of THF, fitted witha reflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 24 h. The mixture was cooled, diluted with ethyl acetate(75 mL) and washed with brine (2×25 mL). The combined organic extractswere dried over sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent) to give 84 mg (32%) of the titlecompound as a brown solid. mp 248°-250°. FDMS: m/e=405. α[D]₅₈₉ =+70.74(c=0.45, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              74.04     74.31                                                H              7.70      7.70                                                 N              10.36     9.85                                                 ______________________________________                                    

EXAMPLE 216(+)-(4aR)-(10bR)-4-methyl-8-(3-fluoro-5-trifluoromethylphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), 1-bromo-3-fluoro-5-trifluoromethylbenzene (158 mg,0.65 mmol), 0.65 mL aqueous sodium carbonate and 2 mL of THF, fittedwith a reflux condenser, and the stirred mixture was heated at 80°,under nitrogen, for 24 h. The mixture was cooled, diluted with ethylacetate (75 mL) and washed with brine (2×25 mL). The combined organicextracts were dried over sodium sulfate, concentrated, and purified bysilica gel chromatography (ethyl acetate eluent) to give 145 mg (57%) ofthe title compound as an oil. FDMS: m/e=391. α[D]₅₈₉ =+67.32 (c=0.55,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              67.51     67.90                                                H              5.41      5.73                                                 N              3.58      3.27                                                 ______________________________________                                    

EXAMPLE 217(+)-(4aR)-(10bR)-4-methyl-8-(5-nitro-2-thienyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), 2-bromo-5-nitrothiophene (135 mg, 0.65 mmol), 0.65mL of 2M aqueous sodium carbonate and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24 h. The mixture was cooled, diluted with ethyl acetate (75 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent) to give 118 mg (51%) of the titlecompound as a white solid. mp 147°-149°. FDMS: m/e=356. α[D]₅₈₉ =+83.48(c=0.54, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              64.02     64.30                                                H              5.66      5.78                                                 N              7.86      7.57                                                 ______________________________________                                    

EXAMPLE 218(+)-(4aR)-(10bR)-4-methyl-8-(5-chloro-2-thienyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), 2-bromo-5-chlorothiophene (128 mg, 0.65 mmol), 0.65mL of 2M aqueous sodium carbonate and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24 h. The mixture was cooled, diluted with ethyl acetate (75 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent) to give 125 mg (56%) of the titlecompound as an oil. FDMS: m/e=345. α[D]₅₈₉ =+74.03 (c=0.51 ,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              66.98     67.39                                                H              5.83      5.90                                                 N              4.05      3.86                                                 ______________________________________                                    

EXAMPLE 219(+)-(4aR)-(10bR)-4-methyl-8-(4-chloro-3-fluorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), 1-bromo-4-chloro-3-fluorobenzene (136 mg, 0.65mmol), 0.65 mL of 2M sodium carbonate and 2 mL of THF, fitted with areflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 24 h. The mixture was cooled, diluted with ethyl acetate(75 mL) and washed with brine (2×25 mL). The combined organic extractswere dried over sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent) to give 125 mg (56%) of the titlecompound as an amorphous foam. FDMS: m/e=357. α[D]₅₈₉ =+74.28 (c=0.35,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              70.48     70.54                                                H              5.91      6.04                                                 N              3.91      3.81                                                 ______________________________________                                    

EXAMPLE 220(+)-(4aR)-(10bR)-4-methyl-8-(4-sulfonamidophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23mg, 0.02 mmol), 4-bromobenzene sulfonamide (153 mg, 0.65 mmol), 0.65 mLof 2M sodium carbonate and 2 mL of THF, fitted with a reflux condenser,and the stirred mixture was heated at 80°, under nitrogen, for 24 h. Themixture was cooled, diluted with ethyl acetate (75 mL) and washed withbrine (2×25 mL). The combined organic extracts were dried over sodiumsulfate, concentrated, and purified by silica gel chromatography (ethylacetate eluent) to give 34 mg (14%) of the title compound as a whitesolid. mp 200° (decomp.) FDMS: m/e=384. α[D]₅₈₉ =+201.8 (c=0.43,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              65.60     65.83                                                H              6.29      6.46                                                 N              7.29      7.52                                                 ______________________________________                                    

EXAMPLE 221 (+)-(4aR)-(10bR)-4-methyl-8-[4-(4-chlorobutyryl)phenyl]-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23mg, 0.02 mmol), 4-bromo-γ-chlorobutyrophenone (170 mg, 0.65 mmol), 0.65mL of 2M aqueous sodium carbonate and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24 h. The mixture was cooled, diluted with ethyl acetate (75 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent) to give 113 mg (42%) of the titlecompound an oil. FDMS: m/e=409. α[D]₅₈₉ =+60.00 (c=0.18, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              73.25     72.91                                                H              6.88      6.80                                                 N              3.42      3.33                                                 ______________________________________                                    

EXAMPLE 222(+)-(4aR)-(10bR)-4-methyl-8-(4-[(2-t-butylcarbonylamino]-5-thienyl]phenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), 5-(4-bromophenyl)-2-(t-butylcarbonylamino)-thiophene(221 mg, 0.65 mmol), 0.65 mL of 2M aqueous sodium carbonate and 2 mL ofTHF, fitted with a reflux condenser, and the stirred mixture was heatedat 80°, under nitrogen, for 24 h. The mixture was cooled, diluted withethyl acetate (75 mL) and washed with brine (2×25 mL). The combinedorganic extracts were dried over sodium sulfate, concentrated, andpurified by silica gel chromatography (ethyl acetate eluent) to give 88mg (28%) of the title compound a brown solid. mp 240° (decomp.) FDMS:m/e=487. α[D]₅₈₉ =+61.73 (c=0.47, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              71.43     71.62                                                H              6.82      7.00                                                 N              8.62      8.05                                                 ______________________________________                                    

EXAMPLE 223(+)-(4aR)-(10bR)-4-methyl-8-(2,3-dioxo-5-indolinyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), 5-bromoisatin hydrate (159 mg, 0.65 mmol), 0.65 mLof 2M sodium carbonate and 2 mL of THF, fitted with a reflux condenser,and the stirred mixture was heated at 80 , under nitrogen, for 24 h. Themixture was cooled, diluted with ethyl acetate (75 mL) and washed withbrine (2×25 mL). The combined organic extracts were dried over sodiumsulfate, concentrated, and purified by silica gel chromatography (5%methanol/ethyl acetate eluent) to give 36 mg (15%) of the title compoundas a white solid. mp >250° FDMS: m/e=374. α[D]₅₈₉ =+75.33 (c=0.53,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              73.78     73.29                                                H              5.92      5.98                                                 N              7.48      7.22                                                 ______________________________________                                    

EXAMPLE 224(+)-(4aR)-(10bR)-4-methyl-8-(2-(2-dimethylaminoethyl)-1H-benzo<de>isoquinolin-6-yl-1,3-(2H)dione)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium (0) (23mg, 0.02 mmol),6-bromo-2-(2-dimethylaminoethyl)-1H-benzo<de>isoquinolin-1,3-(2H)dione(226 mg, 0.65 mmol), 0.65 mL of aqueous sodium carbonate and 2 mL ofTHF, fitted with a reflux condenser, and the stirred mixture was heatedat 80°, under nitrogen, for 48 h. The mixture was cooled, diluted withchloroform (75 mL) and washed with brine (2×25 mL). The combined organicextracts were dried over sodium sulfate, concentrated, and purified bysilica gel chromatography (15% methanol/ethyl acetate eluent) to give141 mg (44%) of the title compound as a white solid. mp 190°-192°. FDMS:m/e=495. α[D]₅₈₉ =+74.71 (c=0.53, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              75.13     74.94                                                H              6.71      6.33                                                 N              8.48      8.22                                                 ______________________________________                                    

EXAMPLE 225(+)-(4aR)-(10bR)-4-methyl-8-(2aR,4S-1-benzoyl-4-dipropylamino-2,2a,3,4-tetrahydrobenz[cd]-1H-indol-7-yl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol),2aR,4S-1-benzoyl-4-dipropylamino-7-iodo(2,2a,3,4-tetrahydrobenz[cd]-1H-indole(317 mg, (3.65 mmol), 0.65 mL of 2M sodium carbonate and 2 mL of THF,fitted with a reflux condenser, and the stirred mixture was heated at80°, under nitrogen, for 24 h. The mixture was cooled, diluted withethyl acetate (75 mL) and washed with brine (2×25 mL). The combinedorganic extracts were dried over sodium sulfate, concentrated, andpurified by silica gel chromatography (5% methanol/ethyl acetate eluent)to give 64 mg (17%) of the title compound as an amorphous foam. mp110°-115°. FDMS: m/e=589. α[D]₅₈₉ =+80.14 (c=0.46, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              79.42     79.58                                                H              8.03      8.06                                                 N              7.12      6.73                                                 ______________________________________                                    

EXAMPLE 226(+)-(4aR)-(10bR)-4-methyl-8-(2aR,4S-1-benzoyl-4-amino-2,2a,3,4-tetrahydrobenz[cd]-1H-indol-7-yl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23mg, 0.02 mmol),2aR,4S-1-benzoyl-4-amino-7-iodo-2,2a,3,4-tetrahydrobenz[cd]-1H-indole(263 mg, 0.65 mmol), 0.65 mL of 2M aqueous sodium carbonate and 2 mL ofTHF, fitted with a reflux condenser, and the stirred mixture was heatedat 80°, under nitrogen, for 24 h. The mixture was cooled, diluted withethyl acetate (75 mL) and washed with brine (2×25 mL). The combinedorganic extracts were dried over sodium sulfate, concentrated, andpurified by silica gel chromatography (5% methanol/ethyl acetate eluent)to give 187 mg (57%) of the title compound as an amorphous foam. mp134°-136°. FDMS: m/e=505.

EXAMPLE 227(+)-(4aR)-(10bR)-4-methyl-8-(3,5-difluorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), 1-bromo-3,5-difluorobenzene (125 mg, 0.65 mmol),0.65 mL of 2M aqueous sodium carbonate and 2 mL of THF, fitted with areflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 24 h. The mixture was cooled, diluted with ethyl acetate(75 mL) and washed with brine (2×25 mL). The combined organic extractswere dried over sodium sulfate, concentrated, and purified by silica gelchromatography (70% ethyl acetate/hexanes eluent) to give 137 mg (62%)of the title compound as an oil. FDMS: m/e=341. α[D]₅₈₉ =+79.29 (c=0.28,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              73.88     73.40                                                H              6.20      6.11                                                 N              4.10      3.99                                                 ______________________________________                                    

EXAMPLE 228(+)-(4aR)-(10bR)-4-methyl-8-(2,6-difluorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), 1-bromo-2,6-difluorobenzene (125 mg, 0.65 mmol),0.65 mL of 2M aqueous sodium carbonate and 2 mL of THF, fitted with areflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 24 h. The mixture was cooled, diluted with ethyl acetate(75 mL) and washed with brine (2×25 mL). The combined organic extractswere dried over sodium sulfate, concentrated, and purified by silica gelchromatography (70% ethyl acetate/hexanes eluent) to give 98 mg (44%) ofthe title compound as an amorphous solid. mp 125°-130°. FDMS: m/e=341.α[D]₅₈₉ =+71.79 (C=0.58, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              73.88     74.13                                                H              6.20      6.32                                                 N              4.10      3.87                                                 ______________________________________                                    

EXAMPLE 229(+)-(4aR)-(10bR)-4-methyl-8-(2,5-difluorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), 1-bromo-2,5-difluorobenzene (125 mg, 0.65 mmol),0.65 mL of 2M sodium carbonate and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24 h. The mixture was cooled, diluted with ethyl acetate (75 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (70% ethyl acetate/hexanes eluent) to give 105 mg (47%)of the title compound as an oil. FDMS: m/e=341. α[D]₅₈₉ =+70.96 (c=0.38,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              73.88     74.01                                                H              6.20      6.43                                                 N              4.10      3.76                                                 ______________________________________                                    

EXAMPLE 230(+)-(4aR)-(10bR)-4-methyl-8-(2,4,6-trifluorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23mg, 0.02 mmol), 1-bromo-2,4,6-trifluorobenzene (137 mg, 0.65 mmol), 0.65mL of 2M aqueous sodium carbonate and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24 h. The mixture was cooled, diluted with ethyl acetate (75 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (70% ethyl acetate/hexanes eluent) to give 116 mg (50%)of the title compound as an oil. FDMS: m/e=359. α[D]₅₈₉ =+68.65 (c=0.35,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              70.18     70.15                                                H              5.61      5.86                                                 N              3.90      3.69                                                 ______________________________________                                    

EXAMPLE 231(+)-(4aR)-(10bR)-4-methyl-8-(2,4-difluorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), 1-bromo-2,4-difluorobenzene (125 mg, 0.65 mmol),0.65 mL of 2M aqueous sodium carbonate and 2 mL of THF, fitted with areflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 24 h. The mixture was cooled, diluted with ethyl acetate(75 mL) and washed with brine (2×25 mL). The combined organic extractswere dried over sodium sulfate, concentrated, and purified by silica gelchromatography (70% ethyl acetate/hexanes eluent) to give 106 mg (48%)of the title compound as white solid. mp 108°-112°. FDMS: m/e=341.α[D]₅₈₉ =+82.90 (c=0.52, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              73.88     73.94                                                H              6.20      6.33                                                 N              4.10      4.05                                                 ______________________________________                                    

EXAMPLE 232(+)-(4aR)-(10bR)-4-methyl-8-(2,3,4-trifluorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), 1-bromo-2,3,4-trifluorobenzene (137 mg, 0.65 mmol),0.65 mL of 2M sodium carbonate and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24 h. The mixture was cooled, diluted with ethyl acetate (75 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (70% ethyl acetate/hexanes eluent) to give 100 mg (43%)of the title compound as a white solid. mp 100°-102°. FDMS: m/e=359.α[D]₅₈₉ =+7837 (c=0.33, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              70.18     70.47                                                H              5.61      5.80                                                 N              3.90      3.78                                                 ______________________________________                                    

EXAMPLE 233(+)-(4aR)-(10bR)-4-methyl-8-(4-[4-nitrobenzyl]thiophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), 4-(4-nitrobenzylthio-1-bromobenzene (211 mg, 0.65mmol), 0.65 mL of sodium carbonate and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 48 h. The mixture was cooled, diluted with chloroform (75 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent) to give 166 mg (54%) of the titlecompound as an oily solid. FDMS: m/e=472. α[D]₅₈₉ =+65.63 (c=0.41,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              71.16     71.63                                                H              5.97      6.21                                                 N              5.93      6.26                                                 ______________________________________                                    

EXAMPLE 234(+)-(4aR)-(10bR)-4-methyl-8-(2-(2-[1-morpholino]ethyl)-1H-benzo<de>isoquinolin-6-yl-1,3-(2H)dione)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a-5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23mg, 0.02 mmol),6-bromo-2-(2-[1-morpholino]ethyl)-1H-benzo<de>iso-quinoline-1,3-(2H)dione(253 mg, 0.65 mmol), 0.65 mL of aqueous sodium carbonate and 2 mL ofTHF, fitted with a reflux condenser, and the stirred mixture was heatedat 80°, under nitrogen, for 48 h. The mixture was cooled, diluted withchloroform (75 mL) and washed with brine (2×25 mL). The combined organicextracts were dried over sodium sulfate, concentrated, and purified bysilica gel chromatography (5% methanol/ethyl acetate eluent) to give 176mg (50%) of the title compound as an amorphous solid. mp 100°-105°.FDMS: m/e=537. α[D]₅₈₉ =+45.10 (c=0.53, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              73.72     73.46                                                H              6.56      6.73                                                 N              7.82      7.55                                                 ______________________________________                                    

EXAMPLE 235(+)-(4aR)-(10bR)-4-methyl-8-(4-pyridinyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), 4-bromopyridine hydrochloride (126 mg, 0.65 mmol),1.30 mL of 2M sodium carbonate and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24 h. The mixture was cooled, diluted with ethyl acetate (75 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (5% methanol/ethyl acetate eluent) to give 85 mg (43%) ofthe title compound as an oil. FDMS: m/e=306.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              78.40     78.56                                                H              7.24      7.00                                                 N              9.14      8.68                                                 ______________________________________                                    

EXAMPLE 236(+)-(4aR)-(10bR)-4-methyl-8-(1-p-toluenesulfonylindol-5-yl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), N-tosyl-5-bromoindole (228 mg, 0.65 mmol), 0.65 mLof sodium carbonate and 2 mL of THF, fitted with a reflux condenser, andthe stirred mixture was heated at 80°, under nitrogen, for 24 h. Themixture was cooled, diluted with ethyl acetate (75 mL) and washed withbrine (2×25 mL). The combined organic extracts were dried over sodiumsulfate, concentrated, and purified by silica gel chromatography (ethylacetate eluent) to give 49 mg (15%) of the title compound as anamorphous foam. FDMS: m/e=498.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              72.26     71.04                                                H              6.06      6.32                                                 N              5.62      4.94                                                 ______________________________________                                    

EXAMPLE 237(+)-(4aR)-(10bR)-4-methyl-8-(1-acetyl-7-nitroindolin-5--yl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), 1-acetyl-5-bromo-7-nitroindoline (185 mg, 0.65mmol), 0.65 mL of 2M sodium carbonate and 2 mL of THF, fitted with areflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 24 h. The mixture was cooled, diluted with ethyl acetate(75 mL) and washed with brine (2×25 mL). The combined organic extractswere dried over sodium sulfate, concentrated, and purified by silica gelchromatography (5% methanol/ethyl acetate eluent) to give 63 mg (22%) ofthe title compound a yellow solid. mp 235°-240°. FDMS: m/e=433. α[D]₅₈₉=+65.72 (c=0.99, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              69.27     69.39                                                H              6.28      6.55                                                 N              9.69      9.54                                                 ______________________________________                                    

EXAMPLE 238(+)-(4aR)-(10bR)-4-methyl-8-(1-acetylindolin-5-yl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium(0) (23mg, 0.02 mmol), 1-acetyl-5-bromoindoline (156 mg, 0.65 mmol), 0.65 mL of2M sodium carbonate and 2 mL of THF, fitted with a reflux condenser, andthe stirred mixture was heated at 80°, under nitrogen, for 24 h. Themixture was cooled, diluted with chloroform (75 mL) and washed withbrine (2×25 mL). The combined organic extracts were dried over sodiumsulfate, concentrated, and purified by silica gel chromatography (5%methanol/ethyl acetate eluent) to give 67 mg (26%) of the title compoundas a yellow solid. mp 197°-200°. FDMS: m/e=388. α[D]₅₈₉ =+77.92 (c=0.36,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              77.29     77.04                                                H              7.26      7.00                                                 N              7.21      7.12                                                 ______________________________________                                    

EXAMPLE 239(+)-(4aR)-(10bR)-4-methyl-8-(8-quinolinyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0 )(23 mg, 0.02 mmol), 8-bromoquinoline (135 mg, 0.65 mmol ), 0.65 mL of 2Msodium carbonate and 2 mL of THF, flitted with a reflux condenser, andthe stirred mixture was heated at 80°, under nitrogen, for 24 h. Themixture was cooled, diluted with ethyl acetate (75 mL) and washed withbrine (2×25 mL). The combined organic extracts were dried over sodiumsulfate, concentrated, and purified by silica gel chromatography (ethylacetate eluent) to give 88 mg (38%) of the title compound as a tansolid. mp 205°-207°. FDMS: m/e=356 α[D]₅₈₉ =+76.28 (c=0.47, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              80.87     80.66                                                H              6.79      6.69                                                 N              7.86      7.76                                                 ______________________________________                                    

EXAMPLE 240(+)-(4aR)-(10bR)-4-methyl-8-(5-quinolinyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0 )(23 mg, 0.02 mmol), 5-bromoquinoline (135 mg, 0.65 mmol ), 0.65 mL of 2Msodium carbonate and 2 mL of THF, fitted with a reflux condenser, andthe stirred mixture was heated at 80°, under nitrogen, for 24 h. Themixture was cooled, diluted with ethyl acetate (75 mL) and washed withbrine (2×25 mL). The combined organic extracts were dried over sodiumsulfate, concentrated, and purified by silica gel chromatography (ethylacetate eluent) to give 128 mg (55%) of the title compound as anamorphous foam. mp 100°-104°. FDMS: m/e=356. α[D]₅₈₉ =+61.77 (c=0.35,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              80.87     79.55                                                H              6.79      6.92                                                 N              7.86      7.60                                                 ______________________________________                                    

EXAMPLE 241(+)-(4aR)-(10bR)-4-methyl-8-(5-isoquinolinyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), 5-bromoisoquinoline (135 mg, 0.65 mmol), 0.65 mL of2M sodium carbonate and 2 mL of THF, fitted with a reflux condenser, andthe stirred mixture was heated at 80°, under nitrogen, for 24 h. Themixture was cooled, diluted with ethyl acetate (75 mL) and washed withbrine (2×25 mL). The combined organic extracts were dried over sodiumsulfate, concentrated, and purified by silica gel chromatography (5%methanol/ethyl acetate eluent) to give 98 mg (42%) of the title compoundas an amorphous solid. mp 182°-184°. FDMS: m/e=356. α[D]₅₈₉ =+57.25(c=0.49, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              80.87     80.28                                                H              6.79      6.86                                                 N              7.86      7.43                                                 ______________________________________                                    

EXAMPLE 242(+)-(4aR)-(10bR)-4-methyl-8-(2-pyridinyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), 2-bromopyridine (103 mg, 0.65 mmol), 0.65 mL of 2Msodium carbonate and 2 mL of THF, fitted with a reflux condenser, andthe stirred mixture was heated at 80°, under nitrogen, for 24 h. Themixture was cooled, diluted with ethyl acetate (75 mL) and washed withbrine (2×25 mL). The combined organic extracts were dried over sodiumsulfate, concentrated, and purified by silica gel chromatography (ethylacetate eluent) to give 98 mg (49%) of the title compound as an oil.FDMS: m/e=306. α[D]₅₈₉ =+83.48 (c=0.38, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              78.40     77.73                                                H              7.24      6.96                                                 N              9.14      9.07                                                 ______________________________________                                    

EXAMPLE 243(+)-(4aR)-(10bR)-4-methyl-8-(2,5-difluoro-4-nitrophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), 1-bromo-2,5-difluoro-4-nitrobenzene (155 mg, 0.65mmol), 0.65 mL of aqueous 2M sodium carbonate solution and 2 mL of THF,fitted with a reflux condenser, and the stirred mixture was heated at80°, under nitrogen, for 24 h. An additional 23 mg of the palladiumreagent was added, and the mixture was heated an additional 24 h. Themixture was cooled, diluted with chloroform (75 mL) and washed withbrine (2×25 mL). The combined organic extracts were dried over sodiumsulfate, concentrated, and purified by silica gel chromatography (ethylacetate eluent) to give 128 mg (51%) of the title compound as anamorphous solid. mp 130°-140°. FDMS: m/e=386. α[D]₅₈₉ =+73.44 (c=0.53,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              65.28     66.70                                                H              5.22      5.69                                                 N              7.25      7.64                                                 ______________________________________                                    

EXAMPLE 244(+)-(4aR)-(10bR)-4-methyl-8-(6-quinolinyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), 6-bromoquinoline (135 mg, 0.65 mmol), 0.65 mL of 2Msodium carbonate and 2 mL of THF, fitted with a reflux condenser, andthe stirred mixture was heated at 80°, under nitrogen, for 24 h. Themixture was cooled, diluted with ethyl acetate (75 mL) and washed withbrine (2×25 mL). The combined organic extracts were dried over sodiumsulfate, concentrated, and purified by silica gel chromatography (5%methanol/ethyl acetate eluent) to give 107 mg (46%) of the titlecompound as an amorphous solid. mp 185°-190°. FDMS: m/e=356. α[D]₅₈₉=+78.73 (c=0.56, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              80.87     80.13                                                H              6.79      6.74                                                 N              7.86      6.99                                                 ______________________________________                                    

EXAMPLE 245(+)-(4aR)-(10bR)-4-methyl-8-(1-hydroxy-5-indanyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), 5-bromo-1-hydroxyindane (138 mg, 0.65 mmol) ,0.65 mLof aqueous 2M sodium carbonate solution and 2 mL of THF, fitted with areflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 16 h. The mixture was cooled, diluted with chloroform (75mL) and washed with brine (2×25 mL). The combined organic extracts weredried over sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent) to give 79 mg (34%) of the titlecompound as an amorphous solid. mp 185°-190°. FDMS: m/e=361. α[D]₅₈₉=+77.38 (c=0.35, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              79.74     79.01                                                H              7.53      7.53                                                 N              3.87      3.79                                                 ______________________________________                                    

EXAMPLE 246(+)-(4aR)-(10bR)-4-methyl-8-[2-(4-[N-benzyl]piperidinyl)-1H-benzo<de>isoquinolin-6-yl-1,3-(2H)dione]-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol),6-bromo-2-(4-[N-benzyl]piperidinyl)-1H-benzo<de>iso-quinoline-1,3-(2H)dione(292 mg, 0.65 mmol), 0.65 mL of aqueous sodium carbonate and 2 mL ofTHF, fitted with a reflux condenser, and the stirred mixture was heatedat 80°, under nitrogen, for 48 h. The mixture was cooled, diluted withchloroform (75 mL) and washed with brine (2×25 mL). The combined organicextracts were dried over sodium sulfate, concentrated, and purified bysilica gel chromatography (ethyl acetate eluent) to give 197 mg (51%) ofthe title compound as an amorphous foam. FDMS: m/e=597. α[D]₅₈₉ =+51.09(c=0.58, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              78.36     76.08                                                H              6.58      6.80                                                 N              7.03      6.40                                                 ______________________________________                                    

EXAMPLE 247(+)-(4aR)-(10bR)-4-methyl-8-(2-quinolinyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), 2-bromoquinoline (135 mg, 0.65 mmol), 0.65 mL of 2Msodium carbonate and 2 mL of THF, fitted with a reflux condenser, andthe stirred mixture was heated at 80°, under nitrogen, for 24 h. Themixture was cooled, diluted with ethyl acetate (75 mL) and washed withbrine (2×25 mL). The combined organic extracts were dried over sodiumsulfate, concentrated, and purified by silica gel chromatography (ethylacetate eluent) to give 126 mg (54%) of the title compound as anamorphous foam. mp 140°-145°. FDMS: m/e=356. α[D]₅₈₉ =+74.01 (c=0.46,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              80.87     80.56                                                H              6.79      6.88                                                 N              7.86      7.45                                                 ______________________________________                                    

EXAMPLE 248(+)-(4aR)-(10bR)-4-methyl-8-(2-oxo-1-benzopyran-6-yl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid 78 mg, 0.65 mmol), tetrakis (triphenylphosphine ) palladium ((23mg, 0.02 mmol), 6-bromocoumarin (146 mg, 0.65 mmol), 0.65 mL of 2Maqueous sodium carbonate and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24 h. The mixture was cooled, diluted with ethyl acetate (75 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent) to give 108 mg (40%) of the titlecompound an amorphous solid. mp 180° (decomp.) FDMS: m/e=373. α[D]₅₈₉=+40.48 (c=0.42, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              77.19     76.90                                                H              6.21      6.48                                                 N              3.75      4.02                                                 ______________________________________                                    

EXAMPLE 249(+)-(4aR)-(10bR)-4-methyl-8-(6-benzothiazolyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid(178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23mg, 0.02 mmol), 6-bromobenzothiazole (139 mg, 0.65 mmol), 0.65 mL of 2Maqueous sodium carbonate and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24 h. The mixture was cooled, diluted with chloroform (75 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (20% ethyl acetate/hexanes eluent) to give 106 mg (47%)of the title compound as an amorphous solid. mp 183°-187°. FDMS:m/e=362. α[D]₅₈₉ =+87.80 (c=0.55, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              72.90     72.63                                                H              6.12      6.30                                                 N              7.73      7.49                                                 ______________________________________                                    

EXAMPLE 250(+)-(4aR)-(10bR)-4-methyl-8-(1-[t-butoxycarbonyl]-5-indolyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), 1-(t-butoxycarbonyl)-5-bromoindole (193 mg, 0.65mmol), 0.65 mL of 2M sodium carbonate and 2 mL of THF, fitted with areflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75mL) and washed with brine (2×25 mL). The combined organic extracts weredried over sodium sulfate, concentrated, and purified by silica gelchromatography (5% methanol/ethyl acetate eluent) to give 113 mg (39%)of the title compound as an amorphous foam. FDMS: m/e=445. α[D]₅₈₉=+68.17 (c=0.47, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              75.65     75.82                                                H              7.25      7.28                                                 N              6.30      5.88                                                 ______________________________________                                    

EXAMPLE 251(+)-(4aR)-(10bR)-4-methyl-8-(2-benzoxazolyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium (0) (23mg, 0.02 mmol), 2-chlorobenzoxazole (110 mg, 0.65 mmol), 0.65 mL of 2Msodium carbonate solution and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 18 h. Additional palladium reagent (23 mg) was added, and themixture was heated an additional 48 h. The mixture was cooled, dilutedwith chloroform (75 mL) and washed with brine (2×25 mL). The combinedorganic extracts were dried over sodium sulfate, concentrated, andpurified by silica gel chromatography (90-100% ethyl acetate/hexaneseluent) to give 45 mg (20%) of the title compound as an amorphous foam.FDMS: m/e=346.

EXAMPLE 252(+)-(4aR)-(10bR)-4-methyl-8-(2-benzothiazolyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), 2-chlorobenzothiazole (110 mg, 0.65 mmol), 0.65 mLof aqueous 2M sodium carbonate solution and 2 mL of THF, fitted with areflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 18 h. The mixture was cooled, diluted with chloroform (75mL) and washed with brine (2×25 mL). The combined organic extracts weredried over sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent) to give 107 mg /45%) of the titlecompound as an amorphous solid. mp 207°-212°. FDMS: m/e=362. α[D]₅₈₉=+88.83 (c=0.60, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              72.90     72.03                                                H              6.12      6.06                                                 N              7.73      7.20                                                 ______________________________________                                    

EXAMPLE 253(+)-(4aR)-(10bR)-4-methyl-8-(2-pyrazinyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), 2-chloropyrazine (74 mg, 0.65 mmol), 0.65 mL of 2Msodium carbonate solution and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 18 h. The mixture was cooled, diluted with chloroform (75 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent) to give 132 mg (66%) of the titlecompound as an amorphous foam. FDMS: m/e=308. α[D]₅₈₉ =+89.71 (c=0.34,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              74.24     73.97                                                H              6.89      6.55                                                 N              13.67     13.50                                                ______________________________________                                    

EXAMPLE 254(+)-(4aR)-(10bR)-4-methyl-8-(2-pyrimidinyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (187 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), 2-chloropyrimidine (74 mg, 0.65 mmol), 0.65 mL of 2Msodium carbonate solution and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 16 h. An additional 23 mg of the palladium reagent was added, andlet stir an additional 16 h. The mixture was cooled, diluted withchloroform (75 mL) and washed with brine (2×25 mL). The combined organicextracts were dried over sodium sulfate, concentrated, and purified bysilica gel chromatography (ethyl acetate eluent) to give 102 mg (51%) ofthe title compound as an amorphous foam. mp 160°-162°. FDMS: m/e=307.α[D]₅₈₉ =+95.71 (c=0.28, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              74.24     73.29                                                H              6.89      6.88                                                 N              13.67     13.52                                                ______________________________________                                    

EXAMPLE 255(+)-(4aR)-(10bR)-4-methyl-8-(2-quinoxalinyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (187 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), 2-chloroquinoxaline (107 mg, 0.65 mmol), 0.65 mL of2M sodium carbonate solution and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen for16 h. Added an additional 23 mg of the palladium reagent, and let stiran additional 16 h. The mixture was cooled, diluted with chloroform (75mL) and washed with brine (2×25 mL). The combined organic extracts weredried over sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent) to give 156 mg (67%) of the titlecompound as a foam. mp 129°-135°. FDMS: m/e=357. α[D]₅₈₉ =+72.94(c=0.63, chloroform).

EXAMPLE 256(+)-(4aR)-(10bR)-4-methyl-8-(2-benzimidazolyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (187 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium (0) (23mg, 0.02 mmol), 2-chlorobenzimidazole (104 mg, 0.68 mmol), 0.65 mL of 2Msodium carbonate solution and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 24 h. An additional 23 mg of the palladium reagent was added, andlet stir an additional 16 h. The mixture was cooled, diluted withchloroform (75 mL) and washed with brine (2×25 mL). The combined organicextracts were dried over sodium sulfate, concentrated, and purified bysilica gel chromatography (0-5% methanol/ethyl acetate eluent gradient)to give 57 mg (25%) of the title compound as an amorphous foam. mp183°-186°. FDMS: m/e=345.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              76.49     75.99                                                H              6.71      6.35                                                 N              12.16     11.69                                                ______________________________________                                    

EXAMPLE 257(+)-(4aR)-(10bR)-4-methyl-8-(3-indazolyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), N-(tBOC)-3-chloroindazole (172 mg, 0.68 mmol), 0.65mL of sodium carbonate and 2 mL of THF, fitted with a reflux condenser,and the stirred mixture was heated at 80°, under nitrogen, for 18 h. Anadditional portion of palladium reagent (0.04 mmol) was added andcontinued heating for an additional 24 h. The mixture was cooled,diluted with chloroform (75 mL), and washed with brine (2×25 mL). Thecombined organic extracts were dried over sodium sulfate, concentrated,and purified by silica gel chromatography (80-100% ethyl acetate/hexanesgradient eluent) to give 49 mg (11%) of the title compound as anamorphous foam. FDMS: m/e=345.

EXAMPLE 258(+)-(4aR)-(10bR)-4-methyl-8-(2-[3-phenyl]tetrazolyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0)(23mg, 0.02 mmol), 2-chloro-3-phenyltetrazole (129 mg, 0.72 mmol), 0.65 mLof 2M sodium carbonate solution and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent) to give 69 mg (28%) of the titlecompound as an amorphous foam. mp 85°-90°. FDMS: m/e=373. α[D]₅₈₉=+84.79 (c=0.65, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              70.76     70.61                                                H              6.21      5.97                                                 N              18.75     18.63                                                ______________________________________                                    

EXAMPLE 259(+)-(4aR)-(10bR)-4-methyl-8-(2-[5-trifluoromethyl]pyridinyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), 2-chloro-5-trifluoromethylpyridine (131 mg, 0.72mmol), 0.65 mL of 2M sodium carbonate and 2 mL of THF, fitted with areflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 24 h. The mixture was cooled, diluted with ethyl acetate(75 mL) and washed with brine (2×25 mL). The combined organic extractswere dried over sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent) to give 141 mg (58%) of the titlecompound as an amorphous foam. mp 65°-68°. FDMS: m/e=374. α[D]₅₈₉=+81.90 (c=0.84, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              67.37     67.12                                                H              5.65      5.68                                                 N              7.48      7.23                                                 ______________________________________                                    

EXAMPLE 260(+)-(4aR)-(10bR)-4-methyl-8-(2-naphtho<1,2-d>thiazolyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), 2-chloronaphtho<1,2-d>thiazole (158 mg, 0.72 mmol),0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with areflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 24 h. Added an additional 23 mg of the palladium reagentand 50 mg of the chloride, and let stir an additional 24 h. The mixturewas cooled, diluted with chloroform (75 mL) and washed with brine (2×25mL). The combined organic extracts were dried over sodium sulfate,concentrated, and purified by silica gel chromatography (ethyl acetateeluent) to give 192 mg (72%) of the title compound as an amorphoussolid. mp 105°-107°. FDMS: m/e=412. α[D]₅₈₉ =+86.44 (c=0.70,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              75.70     75.46                                                H              5.86      5.58                                                 N              6.79      6.55                                                 ______________________________________                                    

EXAMPLE 261(+)-(4aR)-(10bR)-4-methyl-8-(2-[4-fluoro]benzothiazolyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(46 mg, 0.04 mmol), 2-chloro-4-fluorobenzothiazole (154 mg, 0.82 mmol),0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with areflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 48 h. The mixture was cooled, diluted with chloroform (75mL) and washed with brine (2×25 mL). The combined organic extracts weredried over sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent) to give 181 mg (73%) of the titlecompound as an amorphous foam. mp 170°-190°. FDMS: m/e=380. α[D]₅₈₉=+92.40 (c=0.50, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              69.45     69.68                                                H              5.56      5.80                                                 N              7.36      7.07                                                 ______________________________________                                    

EXAMPLE 262(+)-(4aR)-(10bR)-4-methyl-8-(2-[4-chloro]benzothiazolyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenyphosphine) palladium (0) (46mg, 0.04mmol), 2,4-dichlorobenzothiazole (265 mg, 1.30 mmol), 0.65 mL ofaqueous 2M sodium carbonate solution and 2 mL of THF, fitted with areflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 48 h. The mixture was cooled, diluted with chloroform (75mL) and washed with brine (2×25 mL). The combined organic extracts weredried over sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent) to give 177 mg (69%) of the titlecompound as an amorphous solid. mp 206°-209°. m/e=396. α[D]₅₈₉ =+91.10(c=0.81, chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              66.57     66.77                                                H              5.33      5.48                                                 N              7.06      6.97                                                 ______________________________________                                    

EXAMPLE 263(+)-(4aR)-(10bR)-4-methyl-8-(2-[5,6-dichloro]benzothiazolyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(69 mg, 0.06 mmol), 2,5,6-trichlorobenzothiazole (110 mg, 1.13 mmol),0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with areflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 72 h. The mixture was cooled, diluted with chloroform (75mL) and washed with brine (2×25 mL). The combined organic extracts weredried over sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent) to give 113 mg (40%) of the titlecompound as an amorphous foam. FDMS: m/e=431. α[D]₅₈₉ =+79.41 (c=0.79,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              61.26     60.99                                                H              4.67      4.82                                                 N              6.49      6.31                                                 ______________________________________                                    

EXAMPLE 264(+)-(4aR)-(10bR)-4-methyl-8-(2-[4-isopropyl]benzothiazolyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (110 mg, 0.39 mmol), tetrakis (triphenylphosphine)palladium (0) (23mg, 0.04 mmol), 2-chloro-4-isopropylbenzothiazole (110 mg, 0.39 mmol),0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with areflux condenser, and the stirred mixture was heated at 80°, undernitrogen, for 48 h. The mixture was cooled, diluted with chloroform (75mL) and washed with brine (2×25 mL). The combined organic extracts weredried over sodium sulfate, concentrated, and purified by silica gelchromatography (ethyl acetate eluent) to give 94 mg (36%) of the titlecompound as an amorphous solid. mp 170°-180°. FDMS: m/e=404.

EXAMPLE 265(+)-(4aR)-(10bR)-4-methyl-8-(2-[6-chloro]benzothiazolyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one-8-boronicacid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0)(23 mg, 0.02 mmol), 2,6-dichloro benzothiazole (110 mg, 0.65 mmol), 0.65mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a refluxcondenser, and the stirred mixture was heated at 80°, under nitrogen,for 18 h. The mixture was cooled, diluted with chloroform (75 mL) andwashed with brine (2×25 mL). The combined organic extracts were driedover sodium sulfate, concentrated, and purified by silica gelchromatography (80-100% ethyl acetate/hexanes eluent gradient) to give100 mg (39%) of the title compound as a white solid. mp 123°-125°. FDMS:m/e=396. α[D]₅₈₉ =+73.63 (c=1.26, methanol).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              66.57     66.32                                                H              5.33      5.52                                                 N              7.06      7.01                                                 ______________________________________                                    

The following preparation and example illustrate the synthesis ofcompounds of the present invention wherein the X group is an oxygenatom.

PREPARATION 10(+)-(4aR)-(10bR)-4-methyl-8-hydroxy-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

To a suspension of(+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-one-8-boronicacid (1.0 g, 3.7 mmol) in 30 mL of THF was added 3N sodium hydroxide (6mL) followed by 6.0 mL of 30% hydrogen peroxide at -30°. The cold bathwas removed, and the mixture was stirred at room temperature for 2.5 h.Six mL of saturated aqueous sodium sulfite solution was added, followedby 5N hydrochloric acid until solution was acidic. Volatiles wereremoved via rotary evaporation, and the crude solid was heated in ethylacetate and filtered to give 441 mg (53%) of the title compound as anamorphous solid. FDMS m/e=245.

EXAMPLE 266(+)-(4aR)-(10bR)-4-methyl-8-(2-quinolinyloxy)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 50 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-hydroxy-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one(300 mg, 1.22 mmol), tetrabutylammonium chloride (339 mg, 1.22 mmol),2-chloroquinoline (200 mg, 1.22 mmol), 4 mL of 50% sodium hydroxidesolution, and 4 mL of toluene, fitted with a reflux condenser, and thestirred mixture was heated at 100°, under nitrogen, for 24 h. Themixture was cooled, diluted with water (50 mL) and extracted withchloroform (3×100 mL). The combined organic extracts were dried oversodium sulfate, concentrated, and purified by silica gel chromatography(60% ethyl acetate/hexanes eluent; followed by an additionalchromatography on a short silica column, eluting with 10% ethylacetate/dichloromethane) to give 52 mg (11%) of the title compound as awhite solid. mp 172°-174°. FDMS: m/e=372. α[D]₅₈₉ =+67.74 (c=0.43,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              77.39     77.32                                                H              6.49      6.70                                                 N              7.52      7.25                                                 ______________________________________                                    

The following preparation and examples illustrate syntheses of compoundsof the invention wherein the group X incorporates an amino group, andthe synthesis uses a starting material having an amino substituent onthe benzoquinolinone nucleus.

PREPARATION 11(4aR)-(10bR)-8-formamido-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline-3-one

In a sealable, heavy-walled pyrex tube equipped with teflon stirring barwas placed(4aR)-(10bR)-8-bromo-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline-3-one(500 mg, 1.6 mmol), copper(I) iodide (340 mg, 1.8 mmol), powderedpotassium carbonate (500 mg, 3.6 mmol) and formamide (40 mL). Themixture was purged with nitrogen for 10 minutes and the tube sealed. Themixture was heated to 125° for 18 h. After cooling to ambienttemperature, the tube was opened and the contents partitioned betweenwater (250 mL) and ethyl acetate (250 mL). The aqueous phase wasextracted with ethyl acetate (2×100 mL) and the combined organic phasewas dried over anhydrous magnesium sulfate and concentrated to affordcrude 8-formamido intermediate product (220 mg) which was utilizedwithout further purification. m/e 272.

The crude intermediate product was dissolved in ethyl acetate (50 mL),5N hydrochloric acid solution (10 mL) was added and the solution stirredat ambient temperature for 2.5 h. The mixture was made basic withaqueous ammonium hydroxide solution and extracted with ethyl acetate(2×50 mL). The combined organic phase was dried over anhydrous magnesiumsulfate and concentrated to afford crude product (90 mg) which wasutilized without further purification. m/e 244.

EXAMPLE 267(+)-(4aR)-(10bR)-4,10b-dimethyl-8-benzoylamino-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one

A 200 mg portion of(4aR)-(10bR)-4,10b-dimethyl-8-amino-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onewas dissolved in 50 mL of THF and a slight excess of benzoyl chloridewas added. The mixture was stirred at ambient temperature for 3 h, andvolatiles were then removed under vacuum. The resulting oil wastriturated with diethyl ether, and the resulting solids were purified bychromatography on silica gel, eluting with 50% methanol/ethyl acetate. Ayield of 104 mg of solid product was obtained from the column and foundto be the desired product, m.p. 220°-222°. FDMS: m/e=348. α[D]₅₈₉

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              75.83     75.62                                                H              6.94      6.97                                                 N              8.04      7.98                                                 ______________________________________                                    

EXAMPLE 268(+)-(4aR)-(10bR)-4,10b-dimethyl-8-(3-nitrobenzoylamino)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 620 mg portion of(4aR)-(10bR)-4,10b-dimethyl-8-amino-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onewas dissolved in 100 ml of THF, and an equivalent amount of3-nitrobenzoyl chloride (500 mg) was added. The reaction mixture wasstirred for 4 h, and was then evaporated to dryness under vacuum. Theresidue was purified by chromatography on silica gel, eluting with 10%methanol in ethyl acetate, and the product-containing fractions wereevaporated and the resulting solid was crystallized fromdichloromethane/hexane to obtain 595 mg of the desired product, m.p.240°-242°. FDMS: m/e=393. α[D]₅₈₉ =+75.79°.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              67.16     66.92                                                H              5.89      5.86                                                 N              10.68     10.45                                                ______________________________________                                    

EXAMPLE 269(4aR)-(10bR)-4,10b-dimethyl-8-(4-nitrobenzoylamino)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

The same procedure used in Example 268 was repeated, starting with4-nitrobenzoyl chloride, to obtain 38.2 mg of the desired product, m.p.269°-270°. FDMS: m/e=393.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              67.16     66.88                                                H              5.89      5.82                                                 N              10.68     10.59                                                ______________________________________                                    

EXAMPLE 270(4aR)-(10bR)-4,10b-dimethyl-8-(3-aminobenzoylamino)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 200 mg portion of the product of Example 268 was dissolved in ethylacetate and methanol. Twenty ml of 20% aqueous titanium trichloride wasadded, the flask was evacuated and the mixture was stirred at ambienttemperature for 16 h. The mixture was then made basic with ammoniumhydroxide, resulting in an exotherm and the formation of a dark solid.Water was added to break up the solid, and the mixture was extractedwith dichloromethane. The remaining reaction mixture was filtered, andthe solid filter cake was washed with dichloromethane. The organiclayers were collected, dried and concentrated under vacuum. The residuewas recrystallized from dichloromethane/hexane to obtain 190 mg of thedesired product. It was purified by chromatography over silica gel,eluting with ethyl acetate going to 10% methanol/ethyl acetate, andrecrystallized again from dichloromethane/hexane to obtain 80.5 mg ofpurified product, m.p. 154°-156°. FDMS: m/e=363.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              72.70     73.00                                                H              6.93      7.03                                                 N              11.56     11.61                                                ______________________________________                                    

EXAMPLE 271(4aR)-(10bR)-4,10b-dimethyl-8-(4-aminobenzoylamino)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 420 mg portion of the product of Example 269 was reduced as describedin Example 270 above to obtain 30.6 mg of the desired product. FDMS:m/e=363.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              66.07     65.84                                                H              6.55      6.72                                                 N              10.51     10.46                                                ______________________________________                                    

EXAMPLE 272(+)-(4aR)-(10bR)-4-methyl-8-(3-diphenylmethylaminophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

To a solution of(+)-(4aR)-(10bR)-4-methyl-8-(3-aminophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(22 mg, 0.07 mmol), in 0.25 mL of dichloromethane was added benzophenoneimine (1 eq), followed by 1 drop of 1N hydrochloric acid. The mixturewas stirred at room temperature for 1 h, concentrated, and 0.5 mL ofmethanol and sodium cyanoborohydride (0.14 mmol) followed by two dropsof glacial acetic acid was added, and the mixture was stirred for 16 h,diluted with ethyl acetate, rinsed with saturated sodium bicarbonatesolution, and brine. The organic layer was dried over sodium sulfate,concentrated and chromatographed on silica gel (ethyl acetate eluent) togive, after trituration of the resulting oil from ether/hexanes, 28 mg(83%) of the title compound as a white solid. mp 109°-111°. FDMS:m/e=486. α[D]₅₈₉ =+46.90 (c=0.49, methanol).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              83.91     83.62                                                H              7.04      7.14                                                 N              5.76      5.51                                                 ______________________________________                                    

EXAMPLE 273(+)-(4aR)-(10bR)-4-methyl-8-(3-[benzoylamino]phenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-(3-aminophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(50 mg, 0.16 mmol), N,N-dimethylaminopyridine (3 mg, 0,024 mmol),benzoic acid (21 mg, 0.18 mmol), and 0.4 mL of dichloromethane.1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (EDCI) hydrochloride (120mg, 0.64 mmol) was added in one portion, and the mixture was stirred atroom temperature for 10 min. The mixture was diluted withdichloromethane, and the organic phase was washed with water followed bybrine. The organic phase was dried over sodium sulfate, concentrated,and chromatographed on silica gel (0-50% methanol/ethyl acetate eluentgradient) to give 50 mg (76%) of the title compound as an amorphousfoam. mp 257°-262° (decomp.) FDMS m/e=424. α[D]₅₈₉ =+62.50 (c=0.61,chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              79.22     79.62                                                H              6.65      6.50                                                 N              6.60      6.70                                                 ______________________________________                                    

EXAMPLE 274(+)-(4aR)-(10bR)-4-methyl-8-(3-[pivaloylamino]phenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 15 mL round bottom flask was charged with(+)-(4aR)-(10bR)-4-methyl-8-(3-aminophenyl)-10b-methyl1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (31 mg, 0,097 mmol),N,N-dimethylaminopyridine (3 mg, 0,024 mmol), 1 mL of pyridine and 0.5mL of dichloromethane. The solution was cooled to 0°, and excesspivaloyl chloride (0,086 mL, 0.69 mmol) was added. The stirred mixturewas allowed to warm to room temperature over 2 h. The mixture wasdiluted with chloroform, and washed with 5% aqueous hydrochloric acidsolution, water, 5% queous sodium hydroxide solution, water, and thecombined organic extracts were dried over sodium sulfate, concentratedand chromatographed on silica gel (ethyl acetate eluent) to give 25 mg(64%) of the title compound as a yellow solid. mp 95°-98°. FDMS m/e=404.α[D]₅₈₉ =+62.50 (c=0.16, chloroform).

The following group of examples demonstrates typical synthesis ofcompounds having X groups which are alkyl, alkenyl, and alkynyl.

EXAMPLE 275(+)-(4aR)-(10bR)-4-methyl-8-(3-phenylpropyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

To a solution of allylbenzene (106 mg, 0.89 mmol) in 0.5 mL of THF wasadded 9-BBN (0.89 mmol, 1 eguiv) in THF, at 0°. Let stir for 1 h,warming to 5°. To the mixture was added(+)-(4aR)-(10bR)-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(250 mg, 0.812 mmol), triphenyl phosphine (42 mg, 0.16 equiv.),tetrakis(triphenylphosphine) palladium(0) (19 mg, 0.02 equiv.), 1 mL of3N sodium hydroxide solution and an additional 1 mL of THF. Theresulting mixture was heated at 80° for 18 h, cooled, and ethanolaminewas added, followed by ethyl acetate. The resulting organic phase waswashed with brine, dried over sodium sulfate, concentrated, and purifiedby silica gel chromatography (50-100% ethyl acetate/hexanes eluentgradient) to give 160 mg (59%) of the title compound as an oil. FDMSm/e=347.

EXAMPLE 276(+)-(4aR)-(10bR)-4-methyl-8-(2-[2-naphthyl]ethyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

To a solution of 2-vinylnaphthalene (138 mg, 0.89 mmol) in 0.5 mL of THFwas added 9-BBN (0.89 mmol, 1 equiv) in THF, at 0°. Let stir for 1 h,warming to 5°. To the mixture was added(+)-(4aR)-(10bR)-4-H-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(250 mg, 0.812 mmol), triphenyl phosphine, (42 mg, 0.16 equiv.),tetrakis (triphenylphosphine) palladium(0) (19 mg, 0.02 equiv), 1 mL of3N sodium hydroxide solution and an additional 1 mL of THF. Theresulting mixture was heated at 80° for 18 h, cooled, and ethanolaminewas added, followed by ethyl acetate. The resulting organic phase waswashed with brine, dried over sodium sulfate, concentrated, and purifiedby silica gel chromatography (50-100% ethyl acetate/hexanes eluentgradient) to give 186 mg (60%) of the title compound as a tan solid. mp109°-110°. FDMS m/e=383. α[D]₅₈₉ =+46.45 (c=0.66, chloroform).

PREPARATION 12(4aR)-(10bR)-4,10b-dimethyl-8-allyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 9 g portion of(4aR)-(10bR)-4,10b-dimethyl-8-bromo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onewas combined with 11.1 g of tri-n-butyl-2-propenylstannane and 1.69 g oftetrakis(triphenylphosphene) palladium in 40 mL of acetonitrile in asealable tube. Argon was bubbled through the mixture, the cap replaced,and the reaction heated at 90° for 18 h. Upon cooling, the mixture wasfiltered and the filtrate was concentrated under vacuum. The residue wastriturated with diethyl ether to obtain 4.23 g of crystalline product,and a second crop of 1.31 g of product was also obtained. mp 144°-146°.FDMS 255 M+. Calcd for C₁₇ H₂₁ N₁ O₂ :

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              79.96     79.69                                                H              8.29      8.22                                                 N              5.49      5.73                                                 ______________________________________                                    

PREPARATION 13(4aR)-(10bR)-4,10b-dimethyl-8-carboxymethyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one

A 158 mg portion of the product of Preparation 12 was dissolved in 4 mLof acetonitrile, and a solution of 378 mg of sodium periodate in 4 mL ofwater was added, followed by 18 mg of ruthenium trichloride. The mixturewas stirred at ambient temperature for 18 h, and diluted withdichloromethane. The organic layer was removed, and the aqueous layerextracted with dichloromethane. The organic layers were combined, washedwith water, dried, filtered and evaporated to a brown foam. The residuewas dissolved in dichloromethane and extracted with saturated aqueoussodium bicarbonate to which a few milliliters of 10% aqueous sodiumcarbonate had been added. The basic aqueous extract was made acid withhydrochloric acid, and extracted with dichloro-methane. The organiclayer was then dried and evaporated under vacuum to obtain 51 mg of asolid, which was recrystallized from ethyl acetate/hexane to obtain thedesired product in purified form. mp 200°-202°;

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              71.06     71.22                                                H              7.37      7.36                                                 N              4.87      5.00                                                 ______________________________________                                    

EXAMPLE 277(4aR)-(10bR)-4,10b-dimethyl-8-phenylaminocarbonylmethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 200 mg portion of the product of Preparation 13 was dissolved in 5 mLof dimethylformamide, and 135 mg of 1,1'-carbonyldiimidazole was added.The reaction mixture was blanketed with nitrogen, and was stirred atambient temperature for 4 h, at which time 0.1 mL of aniline was added.The solution was then stirred briefly, and concentrated under vacuum.The residue was dissolved in dichloromethane and washed with 1Nhydrochloric acid, 10% sodium sulfate, water and brine. The solution wasthen dried, filtered and evaporated to obtain 220 mg of crude product.It was purified by chromatography on a silica gel column, eluting with3% isopropanol in chloroform. The product-containing fractions werecombined, evaporated and recrystallized from ethyl acetate to obtain thedesired product in pure form. mp 192°-195°. FDMS 362 M+;

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              76.21     75.98                                                H              7.23      7.03                                                 N              7.73      7.81                                                 ______________________________________                                    

EXAMPLE 278(4aR)-(10bR)-4,10b-dimethyl-8-(2-thiophenyl)-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one

Five hundred mg of(4aR)-(10bR)-4,10b-dimethyl-8-bromo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onewas combined with 730 mg of 2-(tri-n-butylstannyl)thiophene and 100 mgof bis(triphenylphosphene) palladium chloride in 6 mL of acetonitrile ina screw capped sealable tube. The mixture was flushed with argon for 5minutes, capped and heated at 90° for 20 h. Upon cooling, the mixturewas filtered and the filtrate was concentrated in vacuum. The residuewas purified by chromatography on a silica gel column, eluting withethyl acetate, and the isolated product was recrystallized from ethylacetate/hexane/chloroform to obtain 167 mg of the desired product. mp193°-195°. FDMS 311.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              73.27     73.32                                                H              6.80      6.94                                                 N              4.50      4.55                                                 ______________________________________                                    

EXAMPLE 279(4aR)-(10bR)-4,10b-dimethyl-8-(2-phenylethenyl)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

Five hundred mg of(4aR)-(10bR)-4,10b-dimethyl-8-bromo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one,4 mg of palladium acetate, 20 mg of tri-o-tolylphosphine, 0.34 mL oftriethylamine and 5 mL of dimethylformamide were placed in a screwcapped sealable tube with a stir bar. The mixture was warmed to 60° andthen 200 mg of styrene was added and the vessel was flushed with argon.The vessel was then capped and heated at 120° for 24 h. The reactionmixture was cooled, diluted with ethyl acetate and filtered and thefiltrate was concentrated under vacuum. The residue was dissolved inchloroform and washed twice with water. The organic layer was dried,filtered and evaporated under vacuum to obtain 400 mg of residue, whichwas recrystallized from ethyl acetate to obtain the desired product.m.p. 173°-175°. FDMS m/e=331.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              83.34     83.12                                                H              7.60      7.64                                                 N              4.23      4.14                                                 ______________________________________                                    

EXAMPLE 280(4aR)-(10bR)-4,10b-dimethyl-8-(2-phenylethyl)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 150 mg portion of the product of Example 279 was hydrogenated on aParr apparatus at 40 p.s.i. in 50 mL of ethanol containing 5 mL ofdimethylformamide and 20 mg of 10% palladium/carbon catalyst. When thestarting material had been consumed, the mixture was filtered and thefiltrate was concentrated under vacuum. The residue was purified bychromatography on silica gel, eluting with 90% ethyl acetate/hexane toobtain a product which was recrystallized from ethyl acetate/hexane toproduce the desired product. m.p. 109°-111°.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              82.84     83.02                                                H              8.16      8.10                                                 N              4.20      4.06                                                 ______________________________________                                    

EXAMPLE 281(4aR)-(10bR)-4,10b-dimethyl-8-(2-[4-isoquinolinyl]ethenyl)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 508 mg portion of(4aR)-(10bR)-4,10b-dimethyl-8-bromo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one,4 mg of palladium acetate, 20 mg of tri-o-tolylphosphine, 0.34 mL oftriethylamine and 5 mL of dimethylformamide were combined in a sealabletube with a stir bar, and the mixture was warmed to 50 under argon. An0.26 g portion of 4-ethenylisoquinoline was added. Then the vessel wasblanketed with argon and sealed and the mixture was heated with stirringat 120° for 20 hours. It was then cooled, and concentrated under vacuumand the residue was purified by chromatography on silica gel, elutingwith 5% isopropanol in chloroform. An 0.29 g portion of an oil wasobtained, which was recrystallized from ethyl acetate/hexane to obtainthe desired product in crystalline form. mp 183°-185°; FDMS 382 M+.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              81.64     81.43                                                H              6.85      6.94                                                 N              7.32      7.22                                                 ______________________________________                                    

EXAMPLE 282(4aR)-(10bR)-4,10b-dimethyl-8-(2-[3-quinolinyl]ethenyl)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 290 mg portion of 3-ethenylquinoline was used in a process otherwisesimilar to that of Example 281 to obtain the title product. mp181°-183°. FDMS 382.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              81.64     81.89                                                H              6.85      6.71                                                 N              7.32      7.55                                                 ______________________________________                                    

EXAMPLE 283(4aR)-(10bR)-4,10b-dimethyl-8-(2-[2-quinolinyl]ethenyl)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

The process of Example 281 was substantially repeated, using 0.34 g of2-ethenylquinoline as the starting material to obtain the title product.mp 233°-236°. FDMS 382.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              81.64     81.42                                                H              6.85      7.00                                                 N              7.32      7.57                                                 ______________________________________                                    

EXAMPLE 284(4aR)-(10bR)-4,10b-dimethyl-8-(2-phenylethynyl)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 1 g portion of(4aR)-(10bR)-4,10b-dimethyl-8-bromo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onewas reacted with 0.4 mL of phenylacetylene in a process substantiallysimilar to that of Example 281 to obtain the desired title product inpure form. mp 205°-208°. FDMS 329.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              83.85     84.07                                                H              7.04      7.05                                                 N              4.25      4.27                                                 ______________________________________                                    

EXAMPLE 6b 285(4aR)-(10bR)-4,10b-dimethyl-8-(2-phenylethenyl)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A 300 mg portion of the product of Example 284 was hydrogenated overpalladium/barium sulfate catalyst in 25 mL of pyridine at 15 psihydrogen pressure at ambient temperature for 1 h. The mixture was thenfiltered and concentrated under vacuum, and the residue was purified bychromatography on silica gel, eluting with 75% ethyl acetate/hexane. Theproduct thereby obtained was further purified on a Chromatatron, elutingwith 5% isopropanol in chloroform to obtain the desired product in theform of a yellow oil. High resolution mass spectroscopy showed thecorrect molecular ion of 332.201440.

EXAMPLE 286(4aR)-(10bR)-8-benzoyl-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A. To a solution of(4aR)-(10bR)-10b-methyl-8-bromo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onein 25 mL of THF at -78° under an atmosphere of nitrogen was added 330 μLof a 1.4M solution of methyllithium in diethyl ether (0.46 mmol). Thereaction mixture turned bright yellow, and after 10 min, 470 μl of a1.7M solution of t-butyllithium in pentane (0.80 mmol) was added. Thereaction mixture was stirred for 10 min before the addition ofbenzaldehyde (80 μL, 0.79 mmol) as a single aliquot. The reaction waswarmed to room temperature and stirred for 30 min before partitioningbetween diethyl ether and 1N hydrochloric acid. The ether layer wasdried over sodium sulfate, filtered and evaporated under reducedpressure to afford 0.1818 g crude product. The material was purified ona Chromatotron (2 mm plate, dry loaded with chloroform, eluted with 5%methanol/chloroform) to give 106 mg of desired product. A portion ofthis material was triturated with diethyl ether to yield a white solid.mp 116-118. FDMS: m/e=321. α[D]₅₈₉ =+100.39

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              78.47     78.45                                                H              7.21      7.26                                                 N              4.36      4.21                                                 ______________________________________                                    

B. To a solution of the alcohol prepared as described above (395 mg, 1.2mmol) in 40 mL of acetone at 0° was added dropwise 1 mL (2.54 mmol) of a2.54M solution of Jones Reagent. The reaction mixture was stirred at 0°for 15 min. before the addition of 2 mL of isopropanol to quench theexcess reagent. The mixture was partitioned between ethyl acetate andbrine. The aqueous layer was extracted with chloroform. The combinedorganic layers were washed with water (100 mL), dried (sodium sulfate),filtered and evaporated under reduced pressure to afford crude product.This material was purified on a chromatotron (2 mm plate, dry loadedwith chloroform, eluted with 5% methanol/chloroform) to give 166 mg ofdesired product (42% yield). This material was methylated using thestandard potassium t-butoxide/methyl iodide in t-butanol method toafford 170 mg crude product. This material was purified on achromatotron (2 mm plate, eluted with ethyl acetate) to give 113 mg ofdesired white solid (65% yield); mp 173°-175°. FDMS: m/e=334. α[D]₅₈₉=80.39 (c=0.5 in chloroform).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              79.25     79.49                                                H              6.95      7.07                                                 N              4.20      4.30                                                 ______________________________________                                    

EXAMPLE 287(4aR)-(10bR)-8-benzyl-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A solution of the hydroxymethyl compound prepared in part A of theexample above, in 80 mL of ethanol with 23.5 mg of 10% Pd/C catalyst,was shaken under an atmosphere of 40 psi of hydrogen for 24 h. Reactionwas not complete and an additional 29 mg of 10% Pd/C was added. After anadditional 48 h, the mixture was filtered through celite andconcentrated under reduced pressure to yield 141 mg of crude productwhich was methylated using the standard potassium t-butoxide/methyliodide in t-butanol method to afford 120 mg of desired product. Thismaterial was purified on a Chromatotron (2 mm plate, eluted with 1%isopropanol in ethyl acetate) to give 87 mg of white solid. Thismaterial was further purified by recrystallization from a 10:1 mixtureof hexane:ethyl acetate to afford 30 mg of product. mp 99°-101° C. FDMS:m/e=319 α[D]₅₈₉ =77.08

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              82.72     82.68                                                H              7.89      7.87                                                 N              4.38      4.33                                                 ______________________________________                                    

EXAMPLE 288(4aR)-(10bR)-8-(2-chlorobenzoyl)-4,10b-dimethyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one

To a solution of(4aR)-(10bR)-10b-methyl-8-bromo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onein 50 mL of THF at -78° under an atmosphere of nitrogen was added 2.25mL of a 1.4M solution of methyllithium in diethyl ether (3.15 mmol).After 10 min, 3.34 mL of a 1.7M solution of t-butyllithium in pentane(5.68 mmol) was added. The reaction mixture was stirred for 10 minbefore the addition of 2-chlorobenzaldehyde (870 mL, 7.72 mmol) as asingle aliquot. The reaction was warmed to room temperature and stirredfor 2 h before partitioning between ethyl acetate and 1N hydrochloricacid. The organic layer was dried, filtered and evaporated under reducedpressure to afford 1.7 g of crude product. The material was purified ona Chromatotron (4 mm plate, dry loaded with chloroform, eluted with 5%methanol/chloroform) to give 435.5 mg of desired product (47% yield): mp105°-115°. FDMS: m/e=355, 357.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              70.88     70.87                                                H              6.23      6.25                                                 N              3.94      3.92                                                 ______________________________________                                    

To a solution of the alcohol prepared as described above (211.7 mg, 0.6mmol) in 25 mL of acetone at 0° was added dropwise 0.5 mL (1.27 mmol) ofa 2.54M solution of Jones Reagent. The reaction mixture was stirred at0° for 30 min before the addition of 2 mL of isopropanol to quench theexcess reagent. The mixture was partitioned between chloroform andbrine. The organic layer was dried, filtered and evaporated underreduced pressure to afford crude product. This material was purified ona Chromatotron (2 mm plate, dry loaded with chloroform, eluted with 5%methanol/chloroform to give 81.0 mg of desired product.

This material was methylated using the standard potassiumt-butoxide/methyl iodide in t-butanol method to afford 160 mg crudeproduct. This material was purified on a Chromatotron (2 mm plate,eluted with 2% methanol/ethyl acetate) followed by a second Chromatotronrun (2 mm plate, eluted with 5% methanol/chloroform) to give 61 mg ofwhite foam after concentration from diethyl ether (65%) yield: mp65°-70°.

EXAMPLE 289(4aR)-(10bR)-8-phenylthiomethyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

A. To a solution of(4aR)-(10bR)-10b-methyl-8-bromo-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-onein 60 mL of THF at -78° under an atmosphere of nitrogen was added 2.9 mLof a 1.4M solution of methyllithium in diethyl ether (4.1 mmol). After20 min, 4.8 mL of a 1.7M solution of t-butyllithium in pentane (8.2mmol) was added. The reaction mixture was stirred for 45 min before theaddition of dimethylformamide (0.63 mL, 8.1 mmol). The reaction waswarmed to room temperature before partitioning between ethyl acetate and1N hydrochloric acid. The organic layer was washed with additional 1Nhydrochloric acid, saturated sodium bicarbonate, brine and then dried(sodium sulfate), filtered and evaporated under reduced pressure toafford 665 mg desired product (80% crude yield). This material was takenon without further purification.

B. To a solution of the aldehyde prepared above (665 mg, 2.73 mmol) in50 mL of absolute ethanol was added 2 equivalents of sodium borohydride(207 mg, 5.4 mmol). The reaction mixture was stirred at room temperaturefor 18 h before the addition of 50 mL of 1N hydrochloric acid. Afterstirring for 1.5 h, ethyl acetate was added and the materialconcentrated to remove ethanol. The residual aqueous layer was extractedwith ethyl acetate and the organic layer was washed with brine, dried(sodium sulfate), and concentrated under reduced pressure to afford 436mg of crude product. This material was purified on a Chromatotron(eluted with 3% methanol/chloroform) to give 310 mg of desired whitesolid (46% yield): mp 176°-177°. FDMS: m/e=245. α[D]₅₈₉ =120.08 (c=0.5in methanol).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              73.44     73.73                                                H              7.81      7.96                                                 N              5.71      5.82                                                 ______________________________________                                    

C. To a solution of the alcohol prepared as described above (462.3 mg,1.88 mmol) in 40 mL of anhydrous acetonitrile was added 0.8 mL of neattrimethylsilyl iodide (5.6 mmol). After 30 minutes, the reaction mixturewas concentrated and the residue partitioned between ethyl acetate andsaturated thiosulfate. The organic layer was washed with brine, dried(sodium sulfate) and concentrated under reduced pressure to yield 664 mgof crude product. This material was purified on a Chromatotron (4 mmplate, eluted with 3% methanol/chloroform) to give 597 mg of desiredsolid (89% yield): mp 215°-217°. FDMS: m/e=355, 228 (m-1). α[D]₅₈₉=99.12 (c=0.5 in methanol). Material was taken on without furtherpurification.

D. To a solution of the iodide prepared as described above (249.4 mg,0.70 mmol) in 25 mL of THF was added a solution of 145 μL ofphenylmercaptan (1.4 mmol) and 210 μL of DBU (1.4 mmol) in 5 mL of THF.After stirring at room temperature for 2 days, the reaction mixture waspartitioned between 1N hydrochloric acid and ethyl acetate. The organiclayer was washed sequentially with 1N hydrochloric acid, 1N sodiumhydroxide, and brine before being dried (sodium sulfate) andconcentrated under reduced pressure to yield 293 mg of crude product.This material was purified on a Chromatotron (4 mm plate, eluted with 3%methanol/chloroform) followed by recrystallization from ethyl acetate togive 166 mg of desired white solid (70% yield): mp 187°-189°. FDMS:m/e=337. α[D]₅₈₉ =82.27 (c=0.5 in methanol).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              74.74     74.97                                                H              6.87      7.11                                                 N              4.15      4.29                                                 ______________________________________                                    

EXAMPLE 290(4aR)-(10bR)-8-(2-benzothiazolyl)thiomethyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

To a solution of the iodomethyl compound prepared in Step C of Example289 in 25 mL of THF was added a solution of 252 mg of2-mercaptobenzothiazole (1.5 mmol) and 226 mL of diazabicycloundecane(DBU) (1.5 mmol) in 5 mL of THF. After stirring at room temperature for2 days, the reaction mixture was partitioned between 1N hydrochloricacid and ethyl acetate. The organic layer was washed sequentially with1N hydrochloric acid, 1N sodium hydroxide, and brine before being dried(sodium sulfate) and concentrated under reduced pressure to yield 382 mgof crude product. This material was purified on a Chromatotron (4 mmplate, eluted with 3% methanol/chloroform) followed by recrystallizationfrom ethyl acetate to give 193 mg of desired white solid. mp 201°-202°.FDMS: m/e=394. α[D]₅₈₉ =75.70

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              66.97     67.23                                                H              5.62      5.82                                                 N              7.10      7.22                                                 ______________________________________                                    

EXAMPLE 291(+)-(4aR)-(10bR)-8-phenylcarboxamido-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinoline-3-one

In a flame-dried 3-neck round bottom flask equipped with magneticstirrer and nitrogen inlet was dissolved(4aR)-(10bR)-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline-3-one(500 mg, 1.7 mmol), in anhydrous THF (50 mL). The solution was cooled to-78° and treated with ethereal methyllithium (1.3 mL, 1.4M, 1.8 mmol)added dropwise over 2 min. After further stirring for 15 min., asolution of t-butyllithium (2.1 mL, 1.7M in pentane, 3.6 mmol) was addeddropwise. Following complete addition, the suspension was treated withphenylisocyanate (418 μL, 3.6 mmol) in a single portion. The mixture waswarmed to ambient temperature and acidified with 1N hydrochloric acidsolution. The mixture was extracted with ethyl acetate and the organicphase washed with brine and dried over anhydrous magnesium sulfate.Removal of solvent and chromatography of the crude product on silica gel(0.5% aqueous ammonium hydroxide/ethyl acetate as eluent) andcrystallization from ethyl acetate afforded product as tan solid. m/e334, OR (c=1.0, MeOH) @589 nM, +100.1°, @365 nM, +308.4°.

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              75.42     75.22                                                H              6.63      6.76                                                 N              8.38      8.25                                                 ______________________________________                                    

EXAMPLE 292(+)-(4aR)-(10bR)-4-methyl-8-(3-diphenylmethylaminomethylphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one

To a suspension of(+)-(4aR)-(10bR)-4-methyl-8-(3-formylphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one(30 mg, 0.09 mmol), in 0.75 mL of methanol was added benzhydryl amine(0.09 mmol), sodium cyanoborohydride (0.09 mmol) and 2 drops of glacialacetic acid (mixture became homogeneous; pH=4). The reaction was stirredat room temperature for 60 h. The mixture was diluted with ethylacetate, saturated aqueous sodium bicarbonate solution was added, andthe resulting mixture was extracted repeatedly with ethyl acetate. Thecombined organic extracts were dried over sodium sulfate, concentrated,and purified by silica gel chromatography (ethyl acetate eluent),followed by trituration of the resulting oil with ether/hexanes, to give36 mg (80%) of the title compound as a white solid. mp 55°-57°. FDMS:m/e=500. α[D]₅₈₉ =+48.40 (c=0.64, methanol).

    ______________________________________                                        Analysis       Calculated                                                                              Found                                                ______________________________________                                        C              83.96     83.42                                                H              7.25      6.92                                                 N              5.60      5.62                                                 ______________________________________                                    

BIOLOGICAL TESTING

Representative compounds of the present invention have been tested instandardized biological test methods in order to determine theiractivity as inhibitors of Type I 5AR.

Activity of the compounds wherein R⁴ and X-R⁵ are absent is shown inU.S. Pat. No. 5,239,075. The activities which are tabulated at columns65-66 of that patent are against Type I 5AR, although it is not soexplicitly stated.

The following test methods are adapted to routine use and may befollowed conveniently by the skilled reader.

Methodology of Human Type I Steroid 5α-Reductase Assays

Preparation of Type I 5α-Reductase from Human Scalp: Scalp punchbiopsies from graft recipient sites were obtained, following the properInformed Consent and Institutional Review Board guidelines, from humanhair transplant procedures immediately after surgery and were frozen ondry ice and stored at -80° C. Approximately 60-75 punches from multiplesurgical procedure were used to generate an enzyme preparation. Thesubcutaneous tissue was cut away and discarded. The skin was frozen withliquid nitrogen and pulverized to powder. The powder was homogenized in30 mL of ice-cold buffer (20 mM Tris-HCl, pH 7.5) using a BrinkmannPolytron (Westbury, N.Y.) with a PTA 10-S probe and a setting of 7. Thehomogenization procedure consisted of four 15 second pulses. Connectivetissue was cleared from the probe with forceps between pulses. Thehomogenate was then filtered through cheese cloth and the filtratecentrifuged at 100,000×g for one hour in a Beckman L8-60Multracentrifuge. The pellet was resuspended by homogenization with aDounce homogenizer using the same buffer solution. An aliquot was takenfor protein determination by the Lowry method, Lowry, et al., ProteinMeasurement with the Folin Phenol Reagent, J. Biol. Chem,, 193, 265-75(1951). Aliquots of the enzyme preparation were stored at -80° untiluse.

Human 5α-Reductase Homogenate Assay: This enzyme assay is based on theconversion of [³ H]-testosterone to [³ H]-5α-dihydrotestosterone (DHT)and other 5α-reduced metabolites. While about 70% of the 5α-reducedmetabolites formed in these assays was DHT, androstanedione was formedat about 30%. Essentially no androsterone was detected. In a totalvolume of 1.0 mL, the Type I assay contained 2.6 μCi [³ H]-testosterone(50 nM), 500 μM of reduced nicotine adenine dinucleotide phosphate, 100mM Tris-HCl, pH 7.5, (in Type II assays, 40 mM sodium acetate at pH 5.5is used instead of Tris-HCl) and test compounds as indicated. Testcompounds were added in 20 μL of dimethylsulfoxide (20 μL ofdimethylsulfoxide was added to blanks and controls). The reaction wasinitiated by the addition of 0.5 mg of Type I 5α-reductase. The reactionmixture was incubated at 25° for 180 min, and terminated by the additionof 1 mL ice-cold stopping solution. The stopping solution contained 40μM each of non-radioactive testosterone, DHT, androstenedione,androstanedione, androsterone, androstan-3β,17β-diol, andandrostan-3α,17β-diol. The samples were prepared for high performanceliquid chromatography by solid phase extraction. Disposable solid matrixextraction columns C-18 reversed phase, 6 mL, 500 mg; Bond Elut™ fromAnalytichem International; Harbor City, Calif.) were conditioned bywashing with 5 mL of methanol followed by 5 mL of deionized water. Thereaction mixtures were then applied to the columns. The columns weresubsequently washed with 5 mL of acetone:water (1:4), followed by 0.3 mLof methanol. The samples were then eluted with 3 mL of methanol andcollected in 20 mL scintillation vials. Three mL of water was then addedto each scintillation vial. The solutions were then transferred to tubesand centrifuged for 30 min at 1000×g to remove any particulate materialbefore chromatography. The [³ H]-testosterone substrate and itsmetabolites were separated by chromatography using a C-18 reversed phasecolumn (Beckman Ultrasphere 5 μm spherical 80A pore, part no. 235329,4.6 mm i.d.×25 mm length) with an isocratic mobile phase (46 water: 46methanol: 8 tetrahydrofuran by volume). The column temperature wasmaintained at 35° and the flow rate was 1.5 mL/min. A 400 μL aliquot wasinjected onto the column and radioactivity was determined using aBeckman 171 in-line flow radioisotope detector in conjunction withRainin Dynamax™ software and a Macintosh computer. The flow rate of theAtomflow™ scintillation fluid was 4.5 mL/min.

While in most instances the compounds listed below have been tested atvarious concentrations, only the test results at 0.3 μM concentrationare shown here, in order to reduce the bulk of the following table. Thedata are reported as percent inhibition of Type I 5AR produced by eachcompound at that concentration, compared to control reaction mixtures.

                  TABLE I                                                         ______________________________________                                        Compound of                                                                   Example No.    Type I                                                         ______________________________________                                        5              44                                                             6              11                                                             7              49                                                             8              22                                                             9              3                                                              10             22                                                             11             87                                                             12             16                                                             13             11                                                             14             37                                                             15             23                                                             16             14                                                             17             29                                                             18             7                                                              19             59                                                             20             22                                                             21             27                                                             22             --                                                             23             59                                                             24             88                                                             25             83                                                             26             86                                                             27             92                                                             28             65                                                             29             78                                                             30             19                                                             31             84                                                             32             71                                                             33             55                                                             34             13                                                             35             17                                                             36             41                                                             37             72                                                             38             84                                                             39             81                                                             40             90                                                             41             88                                                             42             --                                                             43             68                                                             44             --                                                             45             11                                                             46             3                                                              47             --                                                             48             --                                                             49             96                                                             50             95, 94                                                         51             91                                                             52             68                                                             53             100, 66                                                        54             --                                                             55             68                                                             56             92                                                             57             --                                                             58             65                                                             59             --                                                             60             --                                                             61             53                                                             62             45                                                             63             --                                                             64             81                                                             65             79                                                             66             67                                                             67             22                                                             68             31                                                             69             84                                                             70             --                                                             71             80                                                             72             16                                                             73             87                                                             74             16                                                             75             63                                                             76             83                                                             77             88                                                             78             --                                                             79             --                                                             80             76                                                             81             92                                                             82             85                                                             83             --                                                             84             88                                                             85             --                                                             86             66                                                             87             83                                                             88             96                                                             89             --                                                             90             --                                                             91             87                                                             92             --                                                             93             --                                                             94             --                                                             95             95                                                             96             89                                                             97             --                                                             98             76                                                             99             88                                                             100            96                                                             101            75                                                             102            92                                                             103            81                                                             104            89                                                             105            92                                                             106            73                                                             107            80                                                             108            100                                                            109            97                                                             110            97                                                             111            44                                                             112            64                                                             113            70                                                             114            55                                                             115            31                                                             116            --                                                             117            46                                                             118            25                                                             119            84                                                             120            93                                                             121            --                                                             122            --                                                             123            10                                                             124            23                                                             125            64                                                             126            85                                                             127            --                                                             128            82                                                             129            91                                                             130            83                                                             131            57                                                             132            87                                                             133            77                                                             134            97                                                             135            92                                                             136            100                                                            137            90                                                             138            88                                                             139            30                                                             140            --                                                             141            --                                                             142            22                                                             143            63                                                             144            90                                                             145            85                                                             146            13                                                             147            35                                                             148            2                                                              149            58                                                             150            67                                                             151            31                                                             152            47                                                             153            49                                                             154            56                                                             155            58                                                             156            71                                                             157            88                                                             158            78                                                             159            87, 87                                                         160            61                                                             161            71                                                             162            79                                                             163            80                                                             164            85, 87                                                         165            61                                                             166            50                                                             167            62                                                             168            85                                                             169            75                                                             170            --                                                             171            43                                                             172            55                                                             173            65                                                             174            82                                                             175            58                                                             176            25                                                             177            58                                                             178            --                                                             179            61                                                             180            59                                                             181            63                                                             182            63                                                             183            89                                                             184            73                                                             185            88                                                             186            90                                                             187            93                                                             188            88                                                             189            84                                                             190            76                                                             191            65                                                             192            80                                                             193            --                                                             194            --                                                             195            90                                                             196            11                                                             197            --                                                             198            --                                                             199            --                                                             200            59                                                             201            69                                                             202            41                                                             203            8                                                              204            34                                                             205            100                                                            206             97, 100                                                       207            45                                                             208            77                                                             209            24                                                             210            81                                                             211            70                                                             212            73                                                             213            64                                                             214            26                                                             215            84                                                             216            78                                                             217            93                                                             218            84                                                             219            91                                                             220            67                                                             221            95                                                             222            86                                                             223            36                                                             224            71                                                             225            47                                                             226            16                                                             227            97                                                             228            77                                                             229            97                                                             230            86                                                             231            80                                                             232            94                                                             233            95                                                             234            83                                                             235            28                                                             236            84                                                             237            33                                                             238            72                                                             239            42                                                             240            55                                                             241            65                                                             242            5                                                              243            88                                                             244            51                                                             245            54                                                             246            92                                                             247            60                                                             248            54                                                             249            69                                                             250            83                                                             251            69                                                             252            89                                                             253            5                                                              254            37                                                             255            71                                                             256            38                                                             257            36                                                             258            27                                                             259            31                                                             260            84                                                             261            86                                                             262            91                                                             263            56                                                             264            90                                                             265            78                                                             266            57                                                             267            34                                                             268            --                                                             269            8                                                              270            18                                                             271            --                                                             272            86                                                             273            --                                                             274            34                                                             275            75                                                             276            92                                                             277            42                                                             278            --                                                             279            85                                                             280             97, 100                                                       281            75                                                             282            75                                                             283            87                                                             284            86                                                             285            93                                                             286            53                                                             287            82                                                             288            19                                                             289            23                                                             290            25                                                             291            --                                                             292            86                                                             ______________________________________                                    

The methods of treatment of the present invention are mechanisticallyfounded on the outstanding activity of the compounds of Formula I ininhibiting the conversion of testosterone to 5α-dihydrotestosterone byType I 5α-reductase.

Inhibition of Bone Loss

Fracture rate as a consequence of bone loss is inversely correlated withbone mineral density. However, changes in bone density occur slowly, andare measured meaningfully only over many months or years. It ispossible, however, to demonstrate that the formula I compounds with orwithout the coadministration of a bone antiresorptive or anabolic agent,have positive effects on bone mineral density and bone loss by measuringvarious quickly responding biochemical parameters that reflect changesin skeletal metabolism. Typically, patients are treated for a period offrom 8 weeks to 3 years. Blood and urine are collected before, duringand at the conclusion of treatment. Estrogen administration and placebomay serve as the positive and negative controls, respectively.

The patients are either healthy postmenopausal (surgical or natural)women, age 45-65 who would be considered candidates for estrogenreplacement therapy for potential bone loss, or patients of the same agegroup or older who have shown clinical signs of bone loss (e.g.,shortened stature).

Patients who have received any of the following medications at thebeginning of the study are systematically excluded from the study;vitamin D, corticosteroids, hypolipidemics, thiazides, antigout agents,salicylates, phenothiazines, sulfonates, tetracyclines, neomycin, andantihelmintics. Patients who have received any estrogen, progestin, orandrogen treatment more recently than three months prior to thebeginning of the study; patents who have ever received calcitonin,fluoride, or bisphosphonate therapy; patients who have diabetesmellitus; patients who have a cancer history anytime within the previousfive years; patients with any undiagnosed or abnormal genital bleeding;patients with active, or a history of, thromboembolic disorders;patients who have impaired liver or kidney function; patients who haveabnormal thyroid function; patients who are poor medical or psychiatricrisks; or patients who consume an excess of alcohol or abuse drugs.

Patients in the estrogen treatment group, when used, receive 0.625mg/day and the test groups for compounds of formula I receive dosagesfrom 0.1 mg to 50 mg, preferably 1 mg to 20 mg per day, all groupsreceiving oral capsule formulations. Coadministration of a boneantiresorptive agent or an anabolic agent with the administration of aformula I compound also are tested. Coadministration is eitherconcurrent or sequential.

The study is a double-blind design. The investigators and the patientsdo not know the treatment group to which the patient is assigned.

A baseline examination of each patient includes quantitative measurementof urinary calcium, creatinine, hydroxyproline, and pyridinolinecrosslinks. Blood samples are measured for serum levels of osteocalcin,bone-specific alkaline phosphatase, raloxifene, and raloxifenemetabolites. Baseline measurements also include examination of theuterus including uterine biopsy.

During subsequent visits to the investigating physician, measurements ofthe above parameters in response to treatment are repeated.

Subsequent longer term studies can incorporate the direct measurement ofbone density by the use of a photon absorptiometry and the measurementof fracture rates associated with therapy.

In all of the above patients and methods of treatment, the benefit isobtained and the inhibition of bone loss activity through the inhibitionof conversion of testosterone to 5α-dihydrotestosterone in bone cells.The mechanism of efficacy is the inhibition in such cells of theactivity of Type I 5α-reductase.

The term "an effective amount" is used in the present document todescribe the dose of a compound of Formula I, an antiresorptive agentand an anabolic agent, and is defined as the dose which provideseffective treatment or prevention to the patient.

Antiresportive agents are those agents which are known in the art toinhibit the resorption of bone and include, for example, estrogen inwhich estrogens include steroidal compounds having estrogenic activitysuch as, for example, 17β-estradiol, estrone, conjugated estrogen(Premarin®), equine estrogen, 17β-ethynyl estradiol, and the like.Bisphosphonate compounds such as alendronate sodium[4-amino-1-hydroxybutlidine(diphosphoris acid) monosodium salt,trihydrate, and the like, and antiestrogenic compounds such asraloxifene (see, e.g., U.S. Pat. No. 5,393,763) clomiphene,zuclomiphene, enclomiphene, nafoxidene, CI-680, CI-628,CN-55,945-27,Mer-25, U-11, 555A, U-100A, and salts thereof, and the like(see, e.g., U.S. Pat. Nos. 4,729,999 and 4,894,373).

Bone anabolic agents are those agents which are known in the art tobuild bone by increasing the production of the bone protein matrix. Suchanabolic agents include, for example, the various forms of parathyroidhormone (PTH) such as naturally occurring PTH (1-84), PTH (1-34),analogs thereof, and the like.

The administration of compounds of formula I in order to practice thepresent methods of therapy is carried out by administering an effectiveamount of the chosen compound to the patient in need of such treatmentor prophylaxis. The need for a prophylactic administration according tothe methods of the present invention is determined via the use of wellknown risk factors. The effective amount of an individual compound isdetermined, in the final analysis, by the physician in charge of thecase, but depends on factors such as the exact disease to be treated,the severity of the disease and other diseases or conditions from whichthe patient suffers, the chosen route of administration, other drugs andtreatments which the patient may concomitantly require, and otherfactors in the physician's judgment. It will be observed that thecompounds are active at very low concentrations, and hence at low dosagelevels, thereby allowing effective bone loss inhibition with slightprobability of side effects or cross-reactions with other treatments ordrugs. Accordingly, a typical daily dose of a compound of formula I isin the range of from about 0.02 mg to about 100 mg per day. Morepreferred ranges of daily dosage are from about 0.1 mg to about 50 mg,and, more particularly, from about 1 mg to about 20 mg per day. Thecompounds may be administered in a single daily dose, or the daily dosemay be administered in portions at intervals through the day, as ispreferred in the judgment of the physician.

Daily dosage ranges for bone antiresorptive and anabolic agents arethose which are known in the art. The compounds of the methods of thepresent invention can be administered by a variety of routes includingoral, rectal, transdermal, subcutaneous, intravenous, intramuscular, andintranasal, and such compounds are preferably formulated prior toadministration. Therefore, another embodiment of the present inventionis a pharmaceutical formulation comprising an effective amount of acompound of Formula I or a pharmaceutically acceptable salt thereof, abone antiresorptive or anabolic agent, and a pharmaceutically acceptablecarrier, diluent or excipient therefor.

The active ingredient in such formulations comprises from 1% to 99% byweight of the formulation. By "pharmaceutically acceptable" it is meantthe carrier, diluent ore excipient must be compatible with the otheringredients of the formulation and not deleterious to the recipientthereof.

The present pharmaceutical formulations are prepared by known proceduresusing well known and readily available ingredients. In making thecomposition of the present invention, the active ingredient(s) willusually be admixed with a carrier which may be in %he form of a capsule,sachet, paper, or other container. When the carrier serves as a diluent,it may be a solid, semi-solid or liquid material which acts as avehicle, excipient or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions solutions, syrups,aerosols, (as a solid or in a liquid medium), soft and hard gelatincapsules, suppositories, sterile injectable solutions, sterile packagedpowders, and the like.

The following formula%ion examples are illustrative only and are notintended to limit the scope of the invention in any way. "Activeingredient," of course, means a compound according to Formula I or apharmaceutically acceptable salt thereof.

FORMULATION 1

Hard gelatin capsules are prepared using the following ingredients.

    ______________________________________                                                           Quantity                                                                      (mg/capsule)                                               ______________________________________                                        Example 136          20                                                       Starch, dried        400                                                      Magnesium stearate   10                                                       Total                430     mg                                               ______________________________________                                    

FORMULATION 2

A tablet is prepared using the ingredients below:

    ______________________________________                                                            Quantity                                                                      (mg/capsule)                                              ______________________________________                                        Example 280           40                                                      Cellulose, microcrystalline                                                                         600                                                     Silicon dioxide, fumed                                                                              10                                                      Stearate acid         5                                                       Total                 655     mg                                              ______________________________________                                    

The components are blended and compressed to form tablets each weighing665 mg.

    ______________________________________                                        Compound A               10 mg                                                Starch                   70 mg                                                Microcrystalline cellulose                                                                             60 mg                                                Polyvinylpyrrolidone     4 mg                                                 (as 10% solution in water)                                                    Sodium carboxymethyl starch                                                                            4.5 mg                                               Magnesium stearate       0.5 mg                                               Talc                     1 mg                                                 Total                    150 mg                                               ______________________________________                                    

The active ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The aqueous solution containingpolyvinyl--pyrrolidone is mixed with the resultant powder, and themixture then is passed through a No. 14 mesh U.S. sieve. The granules soproduced are dried at 50° C. and passed through a No. 18 mesh U.S.sieve. The sodium carboxymethyl starch, magnesium stearate and talc,previously passed through a No. 60 mesh U.S. sieve, are then added tothe granules which, after mixing, are compressed on a tablet machine toyield tablets each weighing 150 mg.

FORMULATION 4

Capsules, each containing 80 mg of active ingredient, are made asfollows:

    ______________________________________                                        (-)-(4aR)-(10bR)-8-chloro-4-methyl-                                                                     80 mg                                               1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-                                         quinolin-3-one                                                                Starch                    58 mg                                               Microcrystalline cellulose                                                                              58 mg                                               Magnesium stearate        4 mg                                                Total                     200 mg                                              ______________________________________                                    

The active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve, and filled into hardgelatin capsules in 200 mg quantities.

FORMULATION 5

Suppositories, each containing 25 mg of active ingredient per dose, aremade as follows:

    ______________________________________                                        (+)-(4aR)-(10bR)-8-chloro-4,10b-                                                                       25 mg                                                dimethyl-1,2,3,4,4a,5,6,10b-                                                  octahydrobenzo[f]quinolin-3-one                                               Saturated fatty acid glycerid                                                                          2,000 mg                                             Total                    2,025 mg                                             ______________________________________                                    

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.

FORMULATION 6

Suspensions, each containing 50 mg of active ingredient per 5 ml dose,are made as follows:

    ______________________________________                                        8-chloro-4,10b-dimethyl-1,2,3,4,4a,5,                                                                  50     mg                                            6,10b-octahydrobenzo[f]quinolin-3-one                                         Sodium carboxymethyl cellulose                                                                         50     mg                                            Syrup                    1.25   ml                                            Benzoic acid solution    0.10   ml                                            Flavor                   q.v.                                                 Color                    q.v.                                                 Purified water to total  5      ml                                            ______________________________________                                    

The active ingredient is passed through a No. 45 mesh U.S. sieve andmixed with the sodium carboxymethyl cellulose and syrup to form a smoothpaste. The benzoic acid solution, flavor and color are diluted with aportion of the water and added, with stirring. Sufficient water is thenadded to produce the required volume.

FORMULATION 7

An intravenous formulation may be prepared as follows:

    ______________________________________                                        (+)-(4aR)-(10bR)-8,9-dichloro-4,10b-                                                                   10     mg                                            dimethyl-1,2,3,4,4a,5,6,10b-                                                  octahydrobenzo[f]quinolin-3-one                                               Isotonic saline          1,000  ml                                            ______________________________________                                    

The solution of the above ingredients generally is administeredintravenously to a subject at a rate of 1 ml per minute.

FORMULATION 8 Combination Capsule I

    ______________________________________                                        Ingredient          Quantity (mg/capsule)                                     ______________________________________                                        (-)-(4aR)-(10bR)-8-chloro-                                                                        80                                                        4-methyl-1,2,3,4,4a,5,6,10b-                                                  octahydrobenzo[f]-quinolin-3-one                                              Premarin            1                                                         Avicel pH 101       50                                                        Starch 1500         117.50                                                    Silicon Oil         2                                                         Tween 80            0.50                                                      Cab-O-Sil           0.25                                                      ______________________________________                                    

FORMULATION 9 Combination Capsule II

    ______________________________________                                        Ingredient          Quantity (mg/capsule)                                     ______________________________________                                        (-)-(4aR)-(10bR)-8-chloro-                                                                        80                                                        4-methyl-1,2,3,4,4a,5,6,10b-                                                  octahydrobenzo[f]-quinolin-3-one                                              Raloxifene          10-250                                                    Avicel pH 101       50                                                        Starch 1500         117.50                                                    Silicon Oil         2                                                         Tween 80            0.50                                                      Cab-O-Sil           0.25                                                      ______________________________________                                    

FORMULATION 10 Combination Capsule I

    ______________________________________                                        Ingredient          Quantity (mg/capsule)                                     ______________________________________                                        (-)-(4aR)-(10bR)-8-chloro-                                                                        80                                                        4-methyl-1,2,3,4,4a,5,6,10b-                                                  octahydrobenzo[f]-quinolin-3-one                                              Alendronate         0.1-250                                                   Avicel pH 101       50                                                        Starch 1500         117.50                                                    Silicon Oil         2                                                         Tween 80            0.50                                                      Cab-O-Sil           0.25                                                      ______________________________________                                    

FORMULATION 11 Combination Capsule II

    ______________________________________                                        Ingredient          Quantity (mg/capsule)                                     ______________________________________                                        (-)-(4aR)-(10bR)-8-chloro-                                                                        80                                                        4-methyl-1,2,3,4,4a,5,6,10b-                                                  octahydrobenzo[f]-quinolin-3-one                                              PTH (1-84 or 1-34)  0.1-1000                                                  Avicel pH 101       50                                                        Starch 1500         117.50                                                    Silicon Oil         2                                                         Tween 80            0.50                                                      Cab-O-Sil           0.25                                                      ______________________________________                                    

We claim:
 1. A method of inhibiting bone loss comprising administeringto a mammal in need of treatment an effective amount of a compound offormula I ##STR13## wherein R and R¹ both represent hydrogen or combineto form a bond;R² represents hydrogen or C₁ -C₃ alkyl; R³ representshydrogen, methyl or ethyl; either R⁴ and X--R⁵ have the followingdefinitions, (R⁶)_(m) is absent, and R³ does not represent hydrogen; or(R⁶)_(m) has the following definition, R⁴ and X--R⁵ are absent, and R³does not represent ethyl; R⁴ and --X--R⁵ each occupies one of the 7-, 8-and 9-positions; R⁴ represents hydrogen, halo, methyl or ethyl; xrepresents C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₂ -C₄ alkynyl, a bond, --SO--,--SO₂ --, --CO--Y--(CH₂)_(n) --, --Y--CO--(CH₂)_(n), --CO--,--Z--(CH₂)_(n) --, or --SO₃ --; wherein X groups which are notsymmetrical may be in either orientation; Y represents --S--, --O--, or--NH--; Z represents --O-- or --S--; n represents 0-3; R⁵ representsphenyl, naphthalenyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl,anthracenyl, acenaphthalenyl, thiazolyl, benzimidazolyl, indazolyl,thiophenyl, phenanthrenyl, quinolinyl, fluorenyl, isoquinolinyl,indanyl, benzopyranyl, indolyl, benzisoquinolinyl, benzindolyl,benzothiazolyl, benzothiophenyl, quinoxalinyl, benzoxazolyl, metrazolyl,naphthothiazolyl, quinazolinyl, thiazolopyridinyl,pyridazinoquinazolinyl, benzisothiazolyl, benzodioxolyl, benzodioxinyl,diphenylmethyl or triphenylmethyl; the above R⁵ groups are unsubstitutedor substituted with 1-3 groups chosen from the group consisting of halo,trifluoromethyl, trifluoroethoxy, C₁ -C₄ alkyl, trifluoromethoxy,hydroxy, C₁ -C₃ alkoxy, nitro, C₁ -C₃ alkylthio, C₁ -C₆ alkanoyl,phenyl, oxo, phenoxy, phenylthio, C₁ -C₃ alkylsulfinyl, C₁ -C₃alkylsulfonyl, cyano, amino, C₁ -C₃ alkylamino, diphenylmethylamino,triphenylmethylamino, benzyloxy, benzylthio, (mono-halo, nitro orCF₃)benzyl(oxy or thio), di(C₁ -C₃ alkyl, C₃ -C₆ cycloalkyl, or C₄ -C₈cycloalkylalkyl)amino, (mono-C₁ -C₃ alkyl, C₁ -C₃ alkoxy orhalo)-(phenyl, phenoxy, phenylthio, phenylsulfonyl or phenoxysulfonyl),C₂ -C₆ alkanoylamino, benzoylamino, diphenylmethylamino (C₁ -C₃ alkyl),aminocarbonyl, C₁ -C₃ alkylaminocarbonyl, di(C₁ -C₃ alkyl)aminocarbonyl, halo-C₁ -C₆ alkanoyl, aminosulfonyl, C₁ -C₃alkylaminosulfonyl, di(C₁ -C₃ alkyl) aminosulfonyl, phenyl(oxy or thio)(C₁ -C₃ alkyl), (halo, C₁ -C₃ alkyl or C₁ -C₃ alkoxy)phenyl(oxy or thio)(C₁ -C₃ alkyl), benzoyl, or (amino, C₁ -C₃ alkylamino or di(C₁ -C₃alkyl)amino) (C₁ -C₃ alkyl); or an above R⁵ group is substituted with amorpholino(C₁ -C₃ alkyl) group, a phenyl(C₁ -C₃ alkyl)piperidinyl group,a phenyl(C₁ -C₃ alkyl)-piperidinylaminocarbonyl group, a C₂ -C₆alkanoyl-aminothiophenyl group, or a (amino, C₁ -C₃ alkylamino or di(C₁-C₃ alkyl)amino)naphthalenylsulfonylamino group; or R⁵ is aperhalophenyl group; m represents 1-2; R⁶ represents hydrogen, halogen,NO₂, cyano, CF₃, C₁ -C₆ alkyl, C₁ -C₆ alkoxy, carboxy, C₁ -C₆alkoxycarbonyl, amino, C₁ -C₄ alkylamino, C₁ -C₄ dialkylamino, amido, C₁-C₄ alkylamido, C₁ -C₄ dialkylamido, mercapto, C₁ -C₆ alkylthio, C₁ -C₆alkylsulfinyl, C₁ -C₆ alkylsulfonyl, or a group --A--R⁷ where A is C₁-C₆ alkylene C₂ -C₆ alkenylene or C₂ -C₆ alkynylene; and R⁷ representshalogen, hydroxy, CF₃, C₁ -C₆ alkoxy, carboxy, C₁ -C₆ alkoxycarbonyl,amino, C₁ -C₄ alkylamino, C₁ -C₄ dialkylamino, amido, C₁ -C₄ alkylamido,C₁ -C₄ dialkylamido, C₁ -C₄ alkylsulfonylamino, aminosulfonyl or C₁ -C₄alkylaminosulfonyl; or a pharmaceutically acceptable salt thereof.
 2. Amethod according to claim 1 wherein said mammal is a human.
 3. A methodaccording to claim 2 wherein said human is a female.
 4. A method ofclaim 2 wherein the compound is(-)-(4aR)-(10bR)-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.5. A method of claim 2 wherein the compound is(+)-(4aR)-(10bR)-8-chloro-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.6. A method of claim 2 wherein the compound is8-chloro-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one7. A method of claim 2 wherein the compound is(+)-(4aR)-(10bR)-8,9-dichloro-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.8. A method of claim 2 wherein the compound is(+)-(4aR)-(10bR)-4,10b-dimethyl-8-(2-phenylethyl)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.9. A method of claim 2 wherein the compound is(+)-(4aR)-(10bR)-8-benzylthio-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one.10. A method according to claim 2 wherein said administration isprophylactic.
 11. A method for inhibiting bone loss comprising themethod of claim 2 and further comprising administering to said human aneffective amount of a bone antiresorptive agent.
 12. A method accordingto claim 11 wherein said formula I compound is(-)-(4aR)-(10bR)-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one,and said bone antiresorptive agent is estrogen, raloxifene, oralendronate.
 13. A method according to claim 11 wherein said formula Icompound is(+)-(4aR)-(10bR)-8-chloro-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneand said bone antiresorptive agent is estrogen, raloxifene, oralendronate.
 14. A method according to claim 11 wherein said formula Icompound is8-chloro-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]-quinolin-3-oneand said bone antiresorptive agent is estrogen, raloxifene, oralendronate.
 15. A method according to claim 11 wherein said formula Icompound is(+)-(4aR)-(10bR)-8,9-dichloro-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneand said bone antiresorptive agent is estrogen, raloxifene, oralendronate.
 16. A method according to claim 11 wherein said formula Icompound is(+)-(4aR)-(10bR)-4,10b-dimethyl-8-(2-phenylethyl)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneand said bone antiresorptive agent is estrogen, raloxifene, oralendronate.
 17. A method according to claim 11 wherein said formula Icompound is(+)-(4aR)-(10bR)-8-benzylthio-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneand said bone antiresorptive agent is estrogen, raloxifene, oralendronate.
 18. A method for inhibiting bone loss comprising the methodof claim 2 and further comprising administering to said human aneffective amount of a bone anabolic agent.
 19. A method according toclaim 18 wherein said formula I compound is(-)-(4aR)-(10bR)-8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneand said bone anabolic agent is parathyroid hormone (1-84) or (1-34).20. A method according to claim 18 wherein said formula I compound is(+)-(4aR)-(10bR)-8-chloro-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneand said bone anabolic agent is parathyroid hormone (1-84) or (1-34).21. A method according to claim 18 wherein said formula I compound is8-chloro-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneand said bone anabolic agent is parathyroid hormone (1-84) or (1-34).22. A method according to claim 18 wherein said formula I compound is(+)-(4aR)-(10bR)-8,9-dichloro-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneand said bone anabolic agent is parathyroid hormone (1-84) or (1-34).23. A method according to claim 18 wherein said formula I compound is(+)-(4aR)-(10bR)-4,10b-dimethyl-8-(2-phenylethyl)-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneand said bone anabolic agent is parathyroid hormone (1-84) or (1-34).24. A method according to claim 18 wherein said formula I compound is(+)-(4aR)-(10bR)-8-benzylthio-4,10b-dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-oneand said bone anabolic agent is parathyroid hormone (1-84) or (1-34).